Organic compounds

ABSTRACT

The invention relates to particular substituted heterocycle fused gamma-carbolines, their prodrugs, in free, pharmaceutically acceptable salt and/or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of use in the treatment of diseases involving 5-HT 2A  receptor, serotonin transporter (SERT) and/or pathways involving dopamine D 2  receptor signaling systems.

This application claims priority from U.S. Provisional Application No.61/799,405, filed on Mar. 15, 2013, the contents of which areincorporated by reference in their entirety.

FIELD OF THE INVENTION

The invention relates to particular substituted heterocycle fusedgamma-carbolines, in free, pharmaceutically acceptable salt form, theirprodrugs as described herein, pharmaceutical compositions thereof, andmethods of use in the treatment of diseases involving 5-HT_(2A)receptor, serotonin transporter (SERT) and/or pathways involvingdopamine D₂ receptor signaling systems, e.g., diseases or disorders suchas anxiety, psychosis, schizophrenia, sleep disorders, sexual disorders,migraine, conditions associated with cephalic pain, social phobias,gastrointestinal disorders such as dysfunction of the gastrointestinaltract motility and obesity; depression and mood disorders associatedwith psychosis or Parkinson's disease; psychosis such as schizophreniaassociated with depression; bipolar disorder; and other psychiatric andneurological conditions, as well as to combinations with other agents.

BACKGROUND OF THE INVENTION

Certain substituted heterocycle fused gamma-carbolines have beenreported to be agonists or antagonists of 5-HT2 receptors, particularly5-HT_(2A) and 5-HT_(2C) receptors, in treating central nervous systemdisorders. These compounds have been disclosed in U.S. Pat. Nos.6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; U.S. RE39680, andU.S. RE39679, as novel compounds useful for the treatment of disordersassociated with 5-HT_(2A) receptor modulation such as obesity, anxiety,depression, psychosis, schizophrenia, sleep disorders, sexual disordersmigraine, conditions associated with cephalic pain, social phobias,gastrointestinal disorders such as dysfunction of the gastrointestinaltract motility, and obesity. PCT/US08/03340 (WO 2008/112280) and U.S.application Ser. No. 10/786,935 (U.S. Pub. No. 2004/0209864) alsodisclose methods of making substituted heterocycle fusedgamma-carbolines and uses of these gamma-carbolines as serotoninagonists and antagonists useful for the control and prevention ofcentral nervous system disorders such as addictive behavior and sleepdisorders. WO 2009/114181 also discloses of methods of preparingtoluenesulfonic acid addition salt crystals of these substitutedheterocycle fused gamma-carbolines.

In addition, WO/2009/145900 discloses use of particular substitutedheterocycle fused gamma-carbolines for the treatment of a combination ofpsychosis and depressive disorders as well as sleep, depressive and/ormood disorders in patients with psychosis or Parkinson's disease. Inaddition to disorders associated with psychosis and/or depression, thispatent application discloses and claims use of these compounds at a lowdose to selectively antagonize 5-HT_(2A) receptors without affecting orminimally affecting dopamine D₂ receptors, thereby useful for thetreatment of sleep disorders without the side effects of the dopamine D₂pathways or side effects of other pathways (e.g., GABA_(A)receptors)associated with convention sedative-hypnotic agents (e.g.,benzodiazepines) including but not limited to the development of drugdependency, muscle hypotonia, weakness, headache, blurred vision,vertigo, nausea, vomiting, epigastric distress, diarrhea, joint pains,and chest pains.

While these substituted heterocycle fused gamma-carbolines and theiruses have been reported, particularly for the treatment of diseases suchas schizophrenia, patient compliance in adhering to the medicationschedule is a common and critical problem in therapy. According to onestudy, non-compliance with antipsychotic medication is observed inaround 50% of people with schizophrenia. Such non-compliance is linkedto the increase in re-hospitalizations and generally poorer outcome inpeople with psychotic disorders. Therefore, there exists a need fordrugs, particularly anti-psychotic drugs that can overcome thenon-compliance and provide prodrugs which have a sustained or delayedrelease profile.

SUMMARY OF THE INVENTION

The present invention provides prodrugs as well as depot formulation ofparticular substituted heterocycle fused gamma-carbolines that havealtered pharmacokinetic profile, e.g., altered rate of absorption anddistribution, and therefore may be useful for an improved formulationand/or for controlling the duration of the effect of the drug in thebody (e.g., for sustained- or controlled release). The inventiontherefore provides compounds and their prodrugs, their pharmaceuticalcomposition, for use as set forth herein.

In the first aspect, the invention provides a compound of formula I:

wherein:

X is —N(H)—, —N(C₁₋₆alkyl)— or —O—;

Y is —C(O)—, —O— or —C(H)(OR⁴)—;

R⁸ is —C(R^(a))(R^(b))(R^(c)), —O—C(R^(a))(R^(b))(R^(c)) or—N(R^(d))(R^(e));

R^(a), R^(b) and R^(c) are independently H or C₁₋₂₄alkyl;

R^(d) and R^(e) are independently H or C₁₋₂₄alkyl;

R⁶ and R⁷ are independently H or C₁₋₆alkyl;

R⁴ is H or —C(O)—C₁₋₂₁alkyl; and

W⁻ is a pharmaceutically acceptable anion.

In a further embodiment of the first aspect, the invention provides thecompound of Formula I(a) wherein:

X is —N(H)— or —N(CH₃)—;

Y is —C(O)— or —C(H)(OR⁴)—;

R⁸ is —C(R^(a))(R^(b))(R^(c)), —O—C(R^(a))(R^(b))(R^(c)) or—N(R^(d))(R^(e));

R^(a), R^(b) and R^(c) are independently H or C₁₋₂₄alkyl;

R^(d) and R^(e) are independently H or C₁₋₂₄alkyl;

R⁶ and R⁷ are independently H or C₁₋₆alkyl;

R⁴ is H or —C(O)—C₁₋₂₁alkyl; and

W is a pharmaceutically acceptable anion.

In another further embodiment of the first aspect, the inventionprovides the compound of Formula I(b) wherein:

X is —N(CH₃)—;

Y is —C(O)—;

R⁸ is —C(R^(a))(R^(b))(R^(c)), —O—C(R^(a))(R^(b))(R^(c)) or—N(R^(d))(R^(e));

R^(a), R^(b) and R^(c) are independently H or C₁₋₂₄alkyl;

R^(d) and R^(e) are independently H or C₁₋₂₄alkyl;

R⁶ and R⁷ are independently H or C₁₋₆alkyl;

W⁻ is a pharmaceutically acceptable anion.

In yet another further embodiment of the first aspect, the inventionprovides the compound of Formula I, I(a) and I(b) as described in thefollowing formulae:

1.1 the compound of Formula I, wherein X is —N(H)—, —N(C₁₋₆alkyl)— or—O—;

1.2 the compound of Formula I, wherein X is —O—;

1.3 the compound of Formula I, wherein X is —N(C₁₋₆alkyl)—, e.g.,—N(CH₃)—;

1.4 the compound of Formula I, I(a) or I(b), wherein X is —N(CH₃)—;

1.5 the compound of Formula I or I(a), wherein X is —N(H)—;

1.6 the compound of Formula I or any of formulae 1.1-1.5, wherein Y is—C(O)—, —O— or —C(H)(OR⁴)—;

1.7 the compound of Formula I or any of formulae 1.1-1.6, wherein Y is—O—;

1.8 the compound of Formula I, I(a) or I(b) or any of formulae 1.1-1.6,wherein Y is —C(O)—;

1.9 the compound of Formula I or I(a) or any of formulae 1.1-1.6,wherein Y is —C(H)(OR⁴);

1.10 formula 1.9, wherein R⁴ is H or —C(O)—C₁₋₂₁alkyl;

1.11 formula 1.9 or 1.10, wherein R⁴ is H;

1.12 formula 1.9 or 1.10, wherein R⁴ is —C(O)—C₁₋₂₁alkyl (e.g.,—C(O)—C₁₋₅alkyl, —C(O)—C₆₋₁₅alkyl or —C(O)—C₁₆₋₂₁alkyl), preferably saidalkyl is a straight chain, saturated or unsaturated and optionallysubstituted with one or more hydroxy or C₁₋₂₂alkoxy (e.g., ethoxy)groups, for example R⁴ is —C(O)—C₆alkyl, —C(O)—C₇alkyl, —C(O)—C₉alkyl,—C(O)—C₁₁alkyl, —C(O)—C₁₃alkyl or —C(O)—C₁₅alkyl and such compoundhydrolyzes to form the residue of a natural or unnatural, saturated orunsaturated fatty acid, e.g., the compound hydrolyzes to form thehydroxy compound on the one hand and octanoic acid, decanoic acid,dodecanoic acid, tetradecanoic acid or hexadecanoic acid on the otherhand);

1.13 formula 1.9 or 1.10, wherein R⁴ is selected from the groupconsisting of —C(O)—C₆alkyl, —C(O)—C₇alkyl, —C(O)—C₉alkyl,—C(O)—C₁₁alkyl, —C(O)—C₁₃alkyl and —C(O)—C₁₅alkyl;

1.14 formula 1.9 or 1.10, wherein R⁴ is —C(O)—C₁₁alkyl;

1.15 the compound of Formula I, I(a) or I(b) or any of formulae1.1-1.14, wherein R⁸ is —C(R^(a))(R^(b))(R^(c)),—O—C(R^(a))(R^(b))(R^(c)) or —N(R^(d))(R^(e));

1.16 the compound of Formula I, I(a) or I(b) or any of formulae1.1-1.15, wherein R⁸ is C(R^(a))(R^(b))(R^(c));

1.17 the compound of Formula I, I(a) or I(b) or any of formulae1.1-1.15, wherein R⁸ is —O—C(R^(a))(R^(b))(R^(c));

1.18 formula 1.16 or 1.17, wherein R^(a), R^(b) and R^(c) areindependently H or C₁₋₂₄alkyl;

1.19 any of formulae 1.16-1.18, wherein R^(a), R^(b) and R^(c) areindependently C₁₋₂₄alkyl (e.g., selected from the group consisting ofC₂alkyl, C₃alkyl, C₆alkyl, C₈alkyl, C₉alkyl, C₁₁alkyl, C₄alkyl andC₁₉alkyl);

1.20 any of formulae 1.16-1.19, wherein any one of R^(a), R^(b) or R^(c)is H;

1.21 any of formulae 1.16-1.20, wherein one or two of R^(a), R^(b) andR^(c) are independently C₁₋₂₄alkyl (e.g., selected from the groupconsisting of C₂alkyl, C₃alkyl, C₆alkyl, C₈alkyl, C₉alkyl, C₁₁alkyl,C₄alkyl and C₁₉alkyl), and the remaining R^(a), R^(b) and/or R^(c) is H;

1.22 the compound of Formula I, I(a) or I(b) or any of formulae1.1-1.21, wherein R⁸ is —O—C(H)(CH₃)₂;

1.23 the compound of Formula I, I(a) or I(b) or any of formulae1.1-1.21, wherein R⁸ is —C(CH₃)₃;

1.24 the compound of Formula I, I(a) or I(b) or any of formulae1.1-1.15, wherein R⁸ is —N(R^(d))(R^(e)) and R^(d) and R^(e) areindependently H or C₁₋₂₄alkyl;

1.25 formula 1.24, wherein R^(d) or R^(e) is C₁₋₂₄alkyl (e.g., selectedfrom the group consisting of C₂alkyl, C₃alkyl, C₆alkyl, C₈alkyl,C₉alkyl, C₁₁alkyl, C₄alkyl and C₁₉alkyl);

1.26 formula 1.24 or 1.25, wherein R^(d) and R^(e) are independentlyC₁₋₂₄alkyl (e.g., selected from the group consisting of C₂alkyl,C₃alkyl, C₆alkyl, C₈alkyl, C₉alkyl, C₁₁alkyl, C₄alkyl and C₁₉alkyl);

1.27 formula 1.24 or 1.25, wherein one of R^(d) or R^(e) is C₁₋₂₄alkyl(e.g., selected from the group consisting of C₂alkyl, C₃alkyl, C₆alkyl,C₈alkyl, C₉alkyl, C₁₁alkyl, C₄alkyl and C₁₉alkyl) and the other R^(d) orR^(e) is H;

1.28 the compound of Formula I, I(a) or I(b) or any of formulae1.24-1.27, wherein R⁸ is —N(H)(C₆alkyl);

1.29 the compound of Formula I, I(a) or I(b) or any of formulae1.1-1.28, wherein R⁶ and R⁷ are independently H or C₁₋₆alkyl;

1.30 the compound of Formula I, I(a) or I(b) or any of formulae1.1-1.29, wherein R⁶ and R⁷ are both H;

1.31 the compound of Formula I, I(a) or I(b) or any of formula 1.1-1.30,wherein W⁻ is a pharmaceutically acceptable anion;

1.32 the compound of Formula I, I(a) or I(b) or any of formula 1.1-1.31,wherein W⁻ is a pharmaceutically acceptable anion selected from thegroup consisting of: Cl⁻, Br⁻, I⁻, HC(O)O⁻, CH₃C(O)O⁻, CF₃C(O)O⁻, H₂PO₄⁻;

1.33 the compound of Formula I, I(a) or I(b) or any of formulae1.1-1.32, wherein the compound is selected from:

1.34 the compound of Formula I, I(a) or I(b) or any of formulae1.1-1.33, wherein the compound is selected from:

1.35 the compound of Formula I, I(a), I(b) or any of formulae 1.1-1.34,wherein the compound is in substantially pure diastereomeric form (i.e.,substantially free from other diastereomers);

1.36 the compound of Formula I, I(a), I(b) or any of formulae 1.1-1.35,wherein the compound has a diasteromeric excess of greater than 70%,preferably greater than 80%, more preferably greater than 90% and mostpreferably greater than 95%;

1.37 the compound of Formula I, I(a), I(b) or any of theabove-referenced formulae wherein the compound is selected from thegroup consisting of:

1.38 the compound of Formula I, I(a), I(b) or any of theabove-referenced formulae wherein the compound is selected from thegroup consisting of:

In a particular embodiment, the compound is a compound of formula I(b)wherein R⁸ is selected from C₉alkyl, —O—C(H)(CH₃)₂, —C(CH₃)₃ and—N(H)(C₆alkyl).

In the second aspect, the invention provides a compound of Formula II:

wherein:

Y is —C(O)—, —O— or —C(H)(OR⁴)—;

R⁴ is H or —C(O)—C₁₋₂₁alkyl;

R⁵ is —C(O)—O—C(R^(a))(R^(b))(R^(c)) or —C(R⁶)(R⁷)—O—C(O)—R⁸;

R⁸ is —C(R^(a))(R^(b))(R^(c)), —O—C(R^(a))(R^(b))(R^(c)) or—N(R^(d))(R^(e));

R^(a), R^(b) and R^(c) are independently H or C₁₋₂₄alkyl;

R^(d) and R^(e) are independently H or C₁₋₂₄alkyl;

R⁶ and R⁷ are independently H or C₁₋₆alkyl;

in free, salt or prodrug form.

In a further embodiment of the first aspect, the invention provides thecompound of Formula II(a) wherein:

Y is —C(O)— or —C(H)(OR⁴)—;

R⁴ is H or —C(O)—C₁₋₂₁alkyl;

R⁵ is —C(O)—O—C(R^(a))(R^(b))(R^(c)) or —C(R⁶)(R⁷)—O—C(O)—R⁸;

R⁸ is —C(R^(a))(R^(b))(R^(c)), —O—C(R^(a))(R^(b))(R^(c)) or—N(R^(d))(R^(e));

R^(a), R^(b) and R^(c) are independently H or C₁₋₂₄alkyl;

R^(d) and R^(e) are independently H or C₁₋₂₄alkyl;

R⁶ and R⁷ are independently H or C₁₋₆alkyl;

in free, salt or prodrug form.

In a further embodiment of the first aspect, the invention provides thecompound of Formula II(b) wherein:

Y is —C(O)—;

R⁵ is —C(O)—O—C(R^(a))(R^(b))(R^(c)) or —CH₂—O—C(O)—R¹;

R¹ is —C(R^(a))(R^(b))(R^(c)), —O—C(R^(a))(R^(b))(R^(c)) or—N(R^(d))(R^(e));

R^(a), R^(b) and R^(c) are independently H or C₁₋₂₄alkyl;

R^(d) and R^(e) are independently H or C₁₋₂₄alkyl;

R⁶ and R⁷ are independently H or C₁₋₆alkyl;

in free, salt or prodrug form.

In yet another further embodiment of the second aspect, the inventionprovides the compound of Formula II, II(a) and II(b) as described in thefollowing formulae:

2.1. the compound of Formula II, wherein Y is —C(O)—, —O— or—C(H)(OR⁴)—;

2.2. the compound of Formula II or formula 2.1, wherein Y is —O—;

2.3. the compound of Formula II, II(a) or II(b) or formula 2.1, whereinY is —C(O)—;

2.4. the compound of Formula II, II(a) or formula 2.1, wherein Y is—C(H)(OR⁴);

2.5. the compound of Formula II, II(a) or formula 2.4, wherein R⁴ is Hor —C(O)—C₁₋₂₁alkyl;

2.6. the compound of Formula II, II(a) or any of formulae 2.4-2.5,wherein R⁴ is H;

2.7. the compound of Formula II or II(a) or any of formulae 2.4-2.5,wherein R⁴ is —C(O)—C₁₋₂₁alkyl (e.g., —C(O)—C₁₋₅alkyl, —C(O)—C₆₋₁₅alkyl^(or —C(O)—C) ₁₆₋₂₁alkyl), preferably said alkyl is a straight chain,saturated or unsaturated and optionally substituted with one or morehydroxy or C₁₋₂₂alkoxy (e.g., ethoxy) groups, for example R⁴ is—C(O)—C₆alkyl, —C(O)—C₇alkyl, —C(O)—C₉alkyl, —C(O)—C₁₁alkyl,—C(O)—C₁₃alkyl or —C(O)—C₁₅alkyl and such compound hydrolyzes to formthe residue of a natural or unnatural, saturated or unsaturated fattyacid, e.g., the compound hydrolyzes to form the hydroxy compound on theone hand and octanoic acid, decanoic acid, dodecanoic acid,tetradecanoic acid or hexadecanoic acid on the other hand);

2.8. the compound of Formula II or II(a) or any of formulae 2.4-2.5 and2.7, wherein R⁴ is selected from the group consisting of —C(O)—C₆alkyl,—C(O)—C₇alkyl, —C(O)—C₉alkyl, —C(O)—C₁₁alkyl, —C(O)—C₁₃alkyl andC(O)—C₁₅alkyl;

2.9. the compound of Formula II or II(a) or any of formulae 2.4-2.5 and2.7-2.8, wherein R⁴ is —C(O)—C₁₁alkyl;

2.10. the compound of Formula II, II(a) or II(b) or any of formulae2.1-2.9, wherein R⁵ is —C(O)—OC(R^(a))(R^(b))(R^(c)) or—C(R⁶)(R⁷)—O—C(O)—R⁸;

2.11. the compound of Formula II, II(a) or II(b) or any of formulae2.1-2.10, wherein R⁵ is —C(R⁶)(R⁷)—O—C(O)—R⁸ and R⁸ is—O—C(R^(a))(R^(b))(R^(c));

2.12. the compound of Formula II, II(a) or II(b) or any of formulae2.1-2.10, wherein R⁵ is —C(R⁶)(R⁷)—O—C(O)—R⁸ and R⁸ is—C(R^(a))(R^(b))(R^(c));

2.13. any of formulae 2.10-2.12, wherein R^(a), R^(b) and R^(c) areindependently H or C₁₋₂₄alkyl (e.g., selected from the group consistingof C₂alkyl, C₃alkyl, C₆alkyl, C₈alkyl, C₉alkyl, C₁₁alkyl, C₄alkyl andC₁₉alkyl);

2.14. any of formulae 2.10-2.13, wherein R^(a), R^(b) and R^(c) areindependently C₁₋₂₄alkyl (e.g., selected from the group consisting ofC₂alkyl, C₃alkyl, C₆alkyl, C₈alkyl, C₉alkyl, C₁₁alkyl, C₄alkyl andC₁₉alkyl);

2.15. any of formulae 2.10-2.14, wherein R^(a), R^(b) and R^(c) areindependently H;

2.16. any of formulae 2.10-2.15, wherein one or two of R^(a), R^(b) andR^(c) are independently C₁₋₂₄alkyl (e.g., selected from the groupconsisting of C₂alkyl, C₃alkyl, C₆alkyl, C₈alkyl, C₉alkyl, C₁₁alkyl,C₄alkyl and C₁₉alkyl), and the remaining R^(a), R^(b) and/or R^(c) is H;

2.17. the compound of Formula II, II(a) or II(b) or any of formulae2.10-2.16, wherein R⁸ is —O—C(H)(CH₃)₂;

2.18. the compound of Formula II, II(a) or II(b) or any of formulae2.10-2.16, wherein R⁸ is —C(CH₃)₃;

2.19. the compound of Formula II, II(a) or II(b) or any of formulae2.1-2.10, wherein R⁵ is —C(R⁶)(R⁷)—O—C(O)—R⁸ and R⁸ is —N(R^(d))(R^(e));

2.20. formula 2.19, wherein R^(d) and R^(e) are independently H orC₁₋₂₄alkyl;

2.21. formula 2.19 or 2.20, wherein both R^(d) and R^(e) areindependently C₁₋₂₄alkyl (e.g., selected from the group consisting ofC₂alkyl, C₃alkyl, C₆alkyl, C₈alkyl, C₉alkyl, C₁₁alkyl, C₄alkyl andC₁₉alkyl);

2.22. formula 2.19 or 2.20, wherein R^(d) or R^(e) is H;

2.23. formula 2.19 or 2.22, wherein one of R^(d) or R^(e) is C₁₋₂₄alkyl(e.g., selected from the group consisting of C₂alkyl, C₃alkyl, C₆alkyl,C₈alkyl, C₉alkyl, C₁₁alkyl, C₄alkyl and C₁₉alkyl) and the other R^(d) orR^(e) is H;

2.24. the compound of Formula II, II(a) or II(b) or any of formulae2.19-2.23, wherein R⁸ is —N(H)(C₆alkyl);

2.25. the compound of Formula II, II(a) or II(b) or any of formulae2.1-2.24-, wherein R⁶ and R⁷ are independently H or C₁₋₆alkyl;

2.26. the compound of Formula II, II(a) or II(b) or any of formulae2.1-2.24, wherein R⁶ and R⁷ are both H;

2.27. the compound of Formula II, II(a) or II(b) or any of form formulae2.1-2.27, wherein W⁻ is a pharmaceutically acceptable anion;

2.28. the compound of Formula II, II(a) or II(b) or any of formula2.1-2.27, wherein

W⁻ is a pharmaceutically acceptable anion selected from the groupconsisting of: Cl⁻, Br⁻, I⁻, HC(O)O⁻, CH₃C(O)O⁻, CF₃C(O)O⁻, H₂PO₄ ⁻;

2.29. the compound of Formula II, II(a) or II(b) or any of formulae2.1-2.28, wherein the compound is selected from:

2.30. the compound of Formula II, II(a) or II(b) or any of formulae2.1-2.29, wherein the compound is in substantially pure diastereomericform (i.e., substantially free from other diastereomers);

2.31. the compound of Formula II, II(a) or II(b) or any of formulae2.1-2.30, wherein the compound has a diasteromeric excess of greaterthan 70%, preferably greater than 80%, more preferably greater than 90%and most preferably greater than 95%;

in free, salt or prodrug form.

In the third aspect, the invention provides a compound of Formula III:

wherein:

X is —N(H)—, —N(C₁₋₄alkyl)— or —O—;

R⁸ is —C(R^(a))(R^(b))(R^(c)), —O—C(R^(a))(R^(b))(R^(c)) or—N(R^(d))(R^(e));

R^(a), R^(b) and R^(e) are independently H or C₁₋₂₄alkyl;

R^(d) and R^(e) are independently H or C₁₋₂₄alkyl;

R⁶ and R⁷ are independently H or C₁₋₆alkyl;

R¹ is H or C₁₋₆alkyl (e.g., methyl);

R² is H or OR³ wherein R³ is H, C₁₋₆alkyl (e.g., methyl) or—C(O)—C₁₋₂₁alkyl, provided that R¹ and R² are not both H, R¹ and R³ arenot both H, and when R³ is —C(O)—C₁₋₂₁alkyl, R¹ is C₁₋₆alkyl (e.g.,methyl); and

W⁻ is a pharmaceutically acceptable anion.

In a particular embodiment of the third aspect, the compound of FormulaIII is a compound wherein:

X is —N(H)—, —N(C₁₋₄alkyl)— or —O—;

R⁸ is —C(R^(a))(R^(b))(R^(c)), —O—C(R^(a))(R^(b))(R^(c)) or—N(R^(d))(R^(e));

R^(a), R^(b) and R^(e) are independently H or C₁₋₂₄alkyl;

R^(d) and R^(e) are independently H or C₁₋₂₄alkyl;

R⁶ and R⁷ are independently H or C₁₋₆alkyl;

R¹ is H or C₁₋₆alkyl (e.g., methyl);

R² is H or OR³ wherein R³ is H or C₁₋₆alkyl (e.g., methyl), providedthat R¹ and R² are not both H, and R¹ and R³ are not both H; and

W⁻ is a pharmaceutically acceptable anion.

In a further embodiment of the third aspect, the invention provides acompound of Formula III as hereinbefore described as follows:

3.1 the compound of Formula III, wherein R² is OR³, wherein R³ is H,C₁₋₆alkyl (e.g., methyl) or —C(O)—C₁₋₂₁alkyl, provided that R¹ and R²are not both H, R¹ and R³ are not both H, and when R³ is—C(O)—C₁₋₂₁alkyl, R¹ is C₁₋₆alkyl (e.g., methyl);

3.2 the compound of Formula III or 3.1, wherein R¹ is C₁₋₆alkyl (e.g.,methyl);

3.3 the compound of Formula III, 3.1 or 3.2, wherein R¹ is methyl;

3.4 the compound of Formula III or any of formulae 3.1-3.3, wherein R²is OR³ and R³ is C₁₋₆alkyl (e.g., methyl);

3.5 the compound of Formula III or any of formulae 3.1-3.4, wherein R²is OR³ and R³ is methyl;

3.6 the compound of Formula III or any of formulae 3.1-3.3, wherein R²is OR³ and R³ is H, provided that R¹ and R² are not both H and R¹ and R³are not both H;

3.7 the compound of Formula III or any of formulae 3.1-3.3, wherein R²is OR³ and R³ is —C(O)—C₁₋₂₁alkyl;

3.8 the compound of Formula III or any of formulae 3.1-3.7, wherein X isN(H), N(C₁₋₄alkyl) or O;

3.9 the compound of Formula III or any of formulae 3.1-3.7, wherein X is—O—;

3.10 the compound of Formula III or any of formulae 3.1-3.7, wherein Xis —N(H)—;

3.11 the compound of Formula III or any of formulae 3.1-3.7, wherein Xis —N(C₁₋₄alkyl)—;

3.12 the compound of Formula III or any of formulae 3.1-3.7, wherein Xis —N(CH₃)—;

3.13 the Compound of Formula III or any of formulae 3.1-3.12, whereinthe Compound is:

3.14 the Compound of Formula III or any of 3.1-3.12, wherein theCompound is:

3.15 the Compound of Formula III or any of 3.12-3.14, wherein theCompound is in substantially pure diastereomeric form (i.e.,substantially free from other diastereomers);

3.16 the Compound of Formula III or any of 3.1-3.15, wherein theCompound has a diasteromeric excess of greater than 70%, preferablygreater than 80%, more preferably greater than 90% and most preferablygreater than 95%;

3.17 the compound of Formula III or any of 3.1-3.16, wherein R⁸, R^(a),R^(b), R^(c), R^(d), R^(e), R⁶, R⁷ and W⁻ are independently as describedin any of formulae 1.15-1.32;

3.18 the compound of Formula III or any of formulae 3.1-3.17, whereinthe compound is in substantially pure diastereomeric form (i.e.,substantially free from other diastereomers);

3.19 the compound of Formula III or any of formulae 3.1-3.18, whereinthe compound has a diasteromeric excess of greater than 70%, preferablygreater than 80%, more preferably greater than 90% and most preferablygreater than 95%.

In the fourth aspect, the invention provides a compound of Formula IV:

wherein:

R⁵ is —C(O)—O—C(R^(a))(R^(b))(R^(c)) or —C(R⁶)(R⁷)—O—C(O)—R⁸;

R⁸ is C(R^(a))(R^(b))(R^(c)), —O—C(R^(a))(R^(b))(R^(c)) or—N(R^(d))(R^(e));

R^(a), R^(b) and R^(c) are independently H or C₁₋₂₄alkyl;

R^(d) and R^(e) are independently H or C₁₋₂₄alkyl;

R⁶ and R⁷ are independently H or C₁₋₆alkyl;

R¹ is H or C₁₋₆alkyl (e.g., methyl);

R² is H or OR³ wherein R³ is H, C₁₋₆alkyl (e.g., methyl) or—C(O)—C₁₋₂₁alkyl; provided that R¹ and R² are not both H, R¹ and R³ arenot both H, and when R³ is —C(O)—C₁₋₂₁ alkyl, R¹ is C₁₋₆alkyl (e.g.,methyl),

in free, salt or prodrug form.

In a particular embodiment, the compound of Formula IV is a compoundwherein:

R⁵ is —C(O)—O—C(R^(a))(R^(b))(R^(c)) or —C(R⁶)(R⁷)—O—C(O)—R⁸;

R⁸ is —C(R^(a))(R^(b))(R^(c)), —O—C(R^(a))(R^(b))(R^(c)) or—N(R^(d))(R^(e));

R^(a), R^(b) and R^(c) are independently H or C₁₋₂₄alkyl;

R^(d) and R^(e) are independently H or C₁₋₂₄alkyl;

R⁶ and R⁷ are independently H or C₁₋₆alkyl;

R¹ is H or C₁₋₆alkyl (e.g., methyl);

R² is H or OR³ wherein R³ is H or C₁₋₆alkyl (e.g., methyl);

provided that R¹ and R² are not both H, and R¹ and R³ are not both H,

in free, salt or prodrug form.

In a further embodiment of the fourth aspect, the invention provides acompound of Formula IV as hereinbefore described as follows:

4.1. the compound of Formula IV, wherein R⁸, R^(a), R^(b), R^(c), R^(d),R^(e), R⁶, R⁷, R⁵ and are independently as described in any of formulae2.10-2.28;

4.2. the compound of Formula IV or 4.1, wherein R¹, R² and R³ areindependently as described in any of formulae 3.1-3.12;

4.3. the compound of Formula IV or any of formulae 4.1-4.2, wherein thecompound is in substantially pure diastereomeric form (i.e.,substantially free from other diastereomers);

4.4. the compound of Formula IV or any of formulae 4.1-4.2, wherein thecompound has a diasteromeric excess of greater than 70%, preferablygreater than 80%, more preferably greater than 90% and most preferablygreater than 95%.

in free, salt or prodrug form.

The compounds of the present invention, e.g., the compounds of FormulaI, I(a), I(b) or any of formulae 1.1-1.38 as hereinbefore described,Formula II, II(a), II(b) or any of formulae 2.1-2.31, as hereinbeforedescribed; or a compound of Formula III or any of formulae 3.1-3.19 ashereinbefore described; and a compound of Formula IV or any of formulae4.1-4.4 as hereinbefore described, are useful as prodrugs, which may becleaved to release the active compounds. Wherein R⁴ of the compounds ofFormula I et seq. and Formula II et seq. is —C(O)—C₁₋₂₁alkyl, or R³ ofthe compounds of Formula III et seq. and Formula IV et seq. is—C(O)—C₁₋₂₁alkyl, these compounds may exists as a mix prodrug whereinthe —C(O)—C₁₋₂₁alkyl or R⁵ or —C(R⁶)(R⁷)—OC(O)R⁹ may be independentlycleaved off. Upon cleavage, the compounds of Formula I et seq. willrelease the active compound:

wherein X is —N(H)—, N(C₁₋₆alkyl)— or —O—; Y is —C(O)—, —O— or—C(H)(OR⁴)—; and R⁴ is H. Similarly, the compounds of Formula II et seq.will be cleaved to release the active compound:

wherein X is —N(H)—; Y is —C(O)—, —O— or —C(H)(OR⁴)—; and R⁴ is H. Thecompound of Formula III et seq. will be cleaved to release the activecompound:

wherein X is —N(H)—, —N(C₁₋₄alkyl)— or —O—; R¹ is H or C₁₋₆alkyl (e.g.,methyl); and R² is H or OR³ wherein R³ is H, provided that R¹ and R² arenot both H, and R¹ and R³ are not both H. The compound of Formula IV etseq. will be cleaved to release the active compound:

wherein R¹ is H or C₁₋₆alkyl (e.g., methyl); R² is H or OR³ wherein R³is H; provided that R¹ and R² are not both H, and R¹ and R³ are not bothH. The compounds of the invention are believed to provide an extendedrelease of the active compound.

In the fifth aspect, the invention provides a pharmaceutical compositioncomprising a compound of the current invention as hereinbeforedescribed, in admixture with a pharmaceutically acceptable diluent orcarrier. Therefore, in a further embodiment of the fifth aspect, theinvention provides the following:

5.1. A Pharmaceutical Composition comprising the compound of Formula I,I(a), I(b) or any of formulae 1.1-1.38 as hereinbefore described, inadmixture with a pharmaceutically acceptable diluent or carrier(Pharmaceutical Composition 5.1);

5.2. A Pharmaceutical Composition comprising the compound of Formula II,II(a), II(b) or any of formulae 2.1-2.31, in free or pharmaceuticallyacceptable salt form as hereinbefore described, in admixture with apharmaceutically acceptable diluent or carrier (PharmaceuticalComposition 5.2);

5.3. A Pharmaceutical Composition comprising the compound of Formula IIIor any of formulae 3.1-3.19 as hereinbefore described, in admixture witha pharmaceutically acceptable diluent or carrier (PharmaceuticalComposition 5.3);

5.4. A Pharmaceutical Composition comprising the compound of Formula IVor any of formulae 4.1-4.4 as hereinbefore described, in free orpharmaceutically acceptable salt form, in admixture with apharmaceutically acceptable diluent or carrier (PharmaceuticalComposition 5.4);

5.5. A Pharmaceutical Composition comprising the compound of Formula Q:

wherein X is —N(H)—, —N(CH₃)— or —O—; and Y is —C(═O), —O— or —C(H)(OH),in free or pharmaceutically acceptable salt form, in admixture with apharmaceutically acceptable diluent or carrier (PharmaceuticalComposition 5.5).

In a further embodiment of the fifth aspect, the invention provides thePharmaceutical Composition of any of formulae 5.1-5.5, which comprises avehicle comprising an optional viscosity enhancing agent. The drugsubstance or their prodrugs (e.g., the compound disclosed herein) can bedispersed or suspended in the vehicle. The vehicle is preferably anaqueous vehicle which suspends the compounds of the invention disclosedherein. Preferably, the vehicle contains a viscosity enhancing agent.Preferably, these pharmaceutical compositions comprising an optionalviscosity enhancing agent are free or substantially free of sustainedrelease matrices such as macromolecules like albumin present in majoramounts (e.g., 50% by weight or more of total solids), and polymericmatrix like poly lactide-co-glycolide polymers. It is believed thatthese pharmaceutical compositions will provide an extended releaseprofile similar to that obtained by the injection of a polylactide-co-glycolide microsphere formulation containing the activeagent.

Viscous vehicles useful for the fifth aspect can have, for example, aviscosity of at least 20 cp at 20° C. In other embodiments, the fluidphase of the suspension has a viscosity at 20° C. of at least about 30cp, 40 cp, 50 cp, and 60 cp. The viscosity can be achieved by adding aviscosity enhancing agent, such as a carboxymethyl cellulose, such assodium carboxy methylcellulose. The pharmaceutical compositioncomprising a viscosity enhancing agent such as a carboxy methylcelluloseprovides an extended or sustained release for the compound describedherein. In one embodiment, the injection vehicle comprises at leastabout 1% by volume sodium carboxymethyl cellulose, preferably about 3%by volume carboxymethyl cellulose. See U.S. Pat. No. 8,338,427 and U.S.Pat. No. 8,338,428, the contents of each of which are incorporated byreference in their entirety. In one embodiment, the invention providesthe Pharmaceutical Composition 5.5, wherein the compound of Formula Q isa compound wherein X is —N(CH₃)— and Y is —C(═O), in free orpharmaceutically acceptable salt form. In another embodiment, theinvention provides the Pharmaceutical Composition 5.5, wherein thecompound of Formula Q is a compound wherein X is —N(CH₃)— and Y is—C(═O), in free or pharmaceutically acceptable salt form, and theviscosity enhancing agent is sodium carboxy methylcellulose.

In the sixth aspect, the invention provides a pharmaceuticalcomposition, e.g., for sustained or delayed release, e.g., depot,formulation, comprising (i) the compound as described in any of formulae6.1-6.5; and (ii) a polymeric matrix:

6.1. the compound of Formula I, I(a), I(b) or any of formulae 1.1-1.38as hereinbefore described (Pharmaceutical Composition 6.1);

6.2. the compound of Formula II, II(a), II(b) or any of formulae2.1-2.31, in free or pharmaceutically acceptable salt form ashereinbefore described (Pharmaceutical Composition 6.2);

6.3. the compound of Formula III or any of formulae 3.1-3.19 ashereinbefore described (Pharmaceutical Composition 6.3);

6.4. the compound of Formula IV or any of formulae 4.1-4.4 ashereinbefore described, in free or pharmaceutically acceptable salt form(Pharmaceutical Composition 6.4); or

6.5. the compound of Formula Q:

wherein X is —N(H)—, —N(CH₃)— or —O—; and Y is —C(═O), —O— or —C(H)(OH),in free or pharmaceutically acceptable salt form, in admixture with apharmaceutically acceptable diluent or carrier (PharmaceuticalComposition 6.5).

In a further embodiment, the polymeric matrix comprises standardpolymers used in depot formulations such as polymers selected fromapolyester of a hydroxyfatty acid and derivatives thereof, or a polymerof an alkyl alpha-cyanoacrylate, a polyalkylene oxalate, a polyorthoester, a polycarbonate, a polyortho-carbonate, a polyamino acid, ahyaluronic acid ester, and mixtures thereof. In a further embodiment,the polymer is selected from a group consisting of polylactide, polyd,l-lactide, poly glycolide, PLGA 50:50, PLGA 85:15 and PLGA 90:10polymer. In another embodiment, the polymer is selected frompoly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid,copolymers of the foregoing, poly(aliphatic carboxylic acids),copolyoxalates, polycaprolactone, polydioxonone, poly(ortho carbonates),poly(acetals), poly(lactic acid-caprolactone), polyorthoesters,poly(glycolic acid-caprolactone), polyanhydrides, and natural polymersincluding albumin, casein, and waxes, such as, glycerol mono- anddistearate, and the like. In a preferred embodiment, the polymericmatrix comprises poly(d,l-lactide-co-glycolide). For example, thePharmaceutical Composition of any of formulae 6.1-6.5 wherein saidcompound is dissolved or dispersed in a polymeric matrix which comprisesa poly(d,l-lactide-co-glycolide). Any of Pharmaceutical Compositions offormulae 6.1-6.5 as hereinbefore described may be in admixture with apharmaceutically acceptable diluent or carrier.

The pharmaceutical compositions of any of formulae 5.1-5.5 or thepharmaceutical composition of any of formulae 6.1-6.5 are particularlyuseful for sustained or delayed release, wherein the compound isreleased upon degradation of the polymeric matrix and/or the prodrug.Therefore, these compositions may be formulated for controlled- and/orsustained-release of the active compounds as described above over aperiod of up to 180 days, e.g., from about 7 to about 14 to about 30 toabout 180 days. For example, the polymeric matrix may degrade andrelease the compounds disclosed herein over a period of about 7, about14, about 30, about 60 or about 90 days. In another example, thepolymeric matrix may degrade and release the compounds disclosed hereinover a period of about 120, or about 180 days. Therefore, in oneembodiment, the Pharmaceutical Composition of any of formulae 5.1-5.5 or6.1-6.5 releases the compound over a period of up to 180 days, about 120days, about 90 days, about 60 days, about 30 days, about 14 days orabout 7 days.

In still another further embodiment, the Pharmaceutical Compositions ofthe Invention (e.g., any of formulae 5.1-5.5 and any of formulae6.1-6.5) are formulated for administration by injection. In anotherembodiment, the Pharmaceutical Compositions of the Invention (e.g.,Pharmaceutical Composition of any of formulae 5.1-5.5 or 6.1-6.5) may beformulated for oral administration.

In the seventh aspect, the invention provides the compound ashereinbefore described in any of formulae 5.1-5.5 or 6.1-6.5, in anosmotic controlled release oral delivery system (OROS). In a particularembodiment of the seventh aspect, the invention provides a devicecomprising (a) a gelatin capsule containing the compound described inany of formulae 5.1-5.5 or 6.1-6.5; (b) a multilayer wall superposed onthe gelatin capsule comprising, in outward order from the capsule: (i) abarrier layer, (ii) an expandable layer, and (iii) a semipermeablelayer; and (c) and orifice formed or formable through the wall.(Composition P.1) Osmotic controlled release oral delivery system isdescribed in WO 2000/35419 and EP 1 539 115 (U.S. Pub. No.2009/0202631), the contents of each of which applications areincorporated by reference in their entirety.

In another embodiment of the seventh aspect, the invention provides acomposition comprising a gelatin capsule containing a liquid, thecompound as described in any of formulae 5.1-5.5 or 6.1-6.5, the gelatincapsule being surrounded by a composite wall comprising a barrier layercontacting the external surface of the gelatin capsule, an expandablelayer contacting the barrier layer, a semi-permeable layer encompassingthe expandable layer, and an exit orifice formed or formable in thewall. (Composition P.2)

In still another embodiment of the seventh aspect, the inventionprovides a composition comprising a gelatin capsule containing a liquid,the compound as described in any of formulae 5.1-5.5 or 6.1-6.5, thegelatin capsule being surrounded by a composite wall comprising abarrier layer contacting the external surface of the gelatin capsule, anexpandable layer contacting the barrier layer, a semipermeable layerencompassing the expandable layer, and an exit orifice formed orformable in the wall, wherein the barrier layer forms a seal between theexpandable layer and the environment at the exit orifice. (CompositionP.3)

In still another embodiment of the seventh aspect, the inventionprovides a composition comprising a gelatin capsule containing a liquid,the compound as described in any of formulae 5.1-5.5 or 6.1-6.5, thegelatin capsule being surrounded by a barrier layer contacting theexternal surface of the gelatin capsule, an expandable layer contactinga portion of the barrier layer, a semi-permeable layer encompassing atleast the expandable layer, and an exit orifice formed or formable inthe dosage form extending from the external surface of the gelatincapsule to the environment of use. (Composition P.4). The expandablelayer may be formed in one or more discrete sections, such as forexample, two sections located on opposing sides or ends of the gelatincapsule.

In a particular embodiment of the seventh aspect, the compound in theOsmotic-controlled Release Oral delivery System (i.e., in CompositionP.1-P.4) is in a liquid formulation, which formulation may be neat,liquid active agent, liquid active agent in a solution, suspension,emulsion or self-emulsifying composition or the like.

Further information on Osmotic-controlled Release Oral delivery Systemcomposition including characteristics of the gelatin capsule, barrierlayer, an expandable layer, a semi-permeable layer; and orifice may befound in WO 2000/35419, the contents of which are incorporated byreference in their entirety.

Other Osmotic-controlled Release Oral delivery System useful for thecompounds or the Pharmaceutical Compositions of the Invention may befound in EP 1 539 115 (U.S. Pub. No. 2009/0202631), the contents ofwhich are incorporated by reference in their entirety. Therefore, inanother embodiment of the seventh aspect, the invention provides acomposition or device comprising (a) two or more layers, said two ormore layers comprising a first layer and a second layer, said firstlayer comprises the compound as described in any of formulae 5.1-5.5 or6.1-6.5, or a Pharmaceutical Composition as herein before described saidsecond layer comprises a polymer; (b) an outer wall surrounding said twoor more layers; and (c) an orifice in said outer wall. (Composition P.5)

Composition P.5 preferably utilizes a semi-permeable membranesurrounding a three-layer-core: in these embodiments the first layer isreferred to as a first drug layer and contains low amounts of drug(e.g., the compounds disclosed herein) and an osmotic agent such assalt, the middle layer referred to as the second drug layer containshigher amounts of drug, excipients and no salt; and the third layerreferred to as the push layer contains osmotic agents and no drug. Atleast one orifice is drilled through the membrane on the first druglayer end of the capsule-shaped tablet. (Composition P.6)

Composition P.5 or P.6 may comprise a membrane defining a compartment,the membrane surrounding an inner protective subcoat, at least one exitorifice formed or formable therein and at least a portion of themembrane being semi-permeable; an expandable layer located within thecompartment remote from the exit orifice and in fluid communication withthe semi-permeable portion of the membrane; a first drug layer locatedadjacent the exit orifice; and a second drug layer located within thecompartment between the first drug layer and the expandable layer, thedrug layers comprising the compound of the Invention in free orpharmaceutically acceptable salt thereof. Depending upon the relativeviscosity of the first drug layer and second drug layer, differentrelease profiles are obtained. It is important to identify the optimumviscosity for each layer. In the present invention, viscosity ismodulated by addition of salt, sodium chloride. The delivery profilefrom the core is dependent on the weight, formulation and thickness ofeach of the drug layers. (Composition P.7)

In a particular embodiment, the invention provides Composition P.7wherein the first drug layer comprising salt and the second drug layercontaining no salt. Composition P.5-P.7 may optionally comprise aflow-promoting layer between the membrane and the drug layers.

Compositions P.1-P.7 will generally be referred to as Osmotic-controlledRelease Oral delivery System Composition.

In the eighth aspect, the invention provides a method (Method I) for thetreatment or prophylaxis of a central nervous system disorder,comprising administering to a patient in need thereof an effectiveamount of:

8.1. a compound of Formula I, I(a), I(b) or any of formulae 1.1-1.38 ashereinbefore described;

8.2. a compound of Formula II, II(a), II(b) or any of formulae 2.1-2.31,in free or pharmaceutically acceptable salt form as hereinbeforedescribed;

8.3. a compound of Formula III or any of formulae 3.1-3.19 ashereinbefore described;

8.4. a compound of Formula IV or any of formulae 4.1-4.4 as hereinbeforedescribed, in free or pharmaceutically acceptable salt form;

8.5. a Pharmaceutical Composition as described in formula 5.1;

8.6. a Pharmaceutical Composition as described in formula 5.2;

8.7. a Pharmaceutical Composition as described in formula 5.3;

8.8. a Pharmaceutical Composition as described in formula 5.4;

8.9. a Pharmaceutical Composition as described in formula 5.5;

8.10. a Pharmaceutical Composition of any of formulae 6.1-6.5; or

8.11. Composition of any of formulae P.1-P.7 as hereinbefore described;

In a further embodiment of the eighth aspect, the invention providesMethod I or any of Formulae 8.1-8.11, wherein the method is further asdescribed in the following formulae:

8.12. Method I or any of Formulae 8.1-8.11, wherein the central nervoussystem disorder is a disorder selected from a group consisting ofobesity, anxiety, depression (for example refractory depression andMDD), psychosis, schizophrenia, sleep disorders (particularly sleepdisorders associated with schizophrenia and other psychiatric andneurological diseases), sexual disorders, migraine, conditionsassociated with cephalic pain, social phobias, agitation in dementia(e.g., agitation in Alzheimer's disease), agitation in autism andrelated autistic disorders, and gastrointestinal disorders such asdysfunction of the gastrointestinal tract motility;

8.13. Method I or any of Formulae 8.1-8.11, wherein the central nervoussystem disorder is a disorder involving serotonin 5-HT₂A, dopamine D2receptor system and/or serotonin reuptake transporter (SERT) pathways assimilarly described in WO/2009/145900, the contents of which are hereinincorporated by reference in their entirety;

8.14. Method I or any of Formulae 8.1-8.11, wherein the central nervoussystem disorder is a disorder involving serotonin reuptake transporter(SERT) pathways;

8.15. Method I or any of Formulae 8.1-8.11, wherein the central nervoussystem disorder is a disorder selected from the following: (i)psychosis, e.g., schizophrenia, in a patient suffering from depression;(2) depression in a patient suffering from psychosis, e.g.,schizophrenia; (3) mood disorders associated with psychosis, e.g.,schizophrenia or Parkinson's disease; and (4) sleep disorders associatedwith psychosis, e.g., schizophrenia or Parkinson's disease; (5)depression; (6) anxiety; (7) post-traumatic stress disorder; or (8)impulse control disorder, e.g., intermittent explosive disorder, e.g.,in patients suffering from psychosis (e.g., schizophrenia) or dementia;

8.16. Method I or any of Formulae 8.1-8.12, wherein the central nervoussystem disorder is a disorder selected from the following: (i)psychosis, e.g., schizophrenia, in a patient suffering from depression;(2) depression in a patient suffering from psychosis, e.g.,schizophrenia; (3) mood disorders associated with psychosis, e.g.,schizophrenia or Parkinson's disease; and (4) sleep disorders associatedwith psychosis, e.g., schizophrenia or Parkinson's disease;

8.17. Method I or any of Formulae 8.1-8.13, wherein the central nervoussystem disorder is psychosis, e.g., schizophrenia and said patient is apatient suffering from depression;

8.18. Method I or any of Formulae 8.1-8.16, wherein said patient isunable to tolerate the side effects of convention antipsychotic drugs,e.g., chlorpromazine, haloperidol droperidol, fluphenazine, loxapine,mesoridazine molidone, perphenazine, pimozide, prochlorperazinepromazine, thioridazine, thiothixene, trifluoperazine, clozapine,aripiparazole, olanzapine, quetiapine, risperidone and ziprasidone;

8.19. Method I or any of Formulae 8.1-8.17, wherein said patient isunable to tolerate the side effects of convention antipsychotic drugs,e.g., haloperidol, aripiparazole, clozapine, olanzapine, quetiapine,risperidone, and zipasidone;

8.20. Method I or any of Formulae 8.1-8.18, wherein said disorder isdepression and said patient is a patient suffering from psychosis, e.g.,schizophrenia, or Parkinson's disease;

8.21. Method I or any of Formulae 8.1-8.13, wherein said disorder issleep disorder and said patient is suffering from depression;

8.22. Method I or any of 8.1-8.13, wherein said one or more disorders issleep disorder and said patient is suffering from psychosis, e.g.,schizophrenia;

8.23. Method I or any of 8.1-8.13, wherein said one or more disorders issleep disorder and said patient is suffering from Parkinson's disease;

8.24. Method I or any of 8.1-8.13, wherein said one or more disorders issleep disorder and said patient is suffering from depression andpsychosis, e.g., schizophrenia, or Parkinson's disease.

8.25. Any of the foregoing methods, wherein the effective amount is 1mg-1000 mg, preferably 2.5 mg-50 mg, in free or pharmaceuticallyacceptable salt, non-prodrug form, per day;

8.26. Any of the foregoing methods, wherein the effective amount is 1mg-100 mg per day, preferably 2.5 mg-50 mg, in free or pharmaceuticallyacceptable salt, non-prodrug form, per day;

8.27. Any of the foregoing methods wherein a condition to be treated isdyskinesia, e.g. in a patient receiving dopaminergic medications, e.g.,medications selected from levodopa and levodopa adjuncts (carbidopa,COMT inhibitors, MAO-B inhibitors), dopamine agonists, andanticholinergics, e.g., levodopa;

8.28. Any of the foregoing methods wherein the patient suffers fromParkinson's disease;

8.29. Any of the foregoing methods wherein the patient does not respondto a selective serotonin re-uptake inhibitor, e.g. selected from one ormore of citalopram (Celexa, Cipramil, Cipram, Dalsan, Recital, Emocal,Sepram, Seropram, Citox, Cital); dapoxetine (Priligy); escitalopram(Lexapro, Cipralex, Seroplex, Esertia); fluoxetine (Depex, Prozac,Fontex, Seromex, Seronil, Sarafem, Ladose, Motivest, Flutop, Fluctin(EUR), Fluox (NZ), Depress (UZB), Lovan (AUS), Prodep (IND));fluvoxamine (Luvox, Fevarin, Faverin, Dumyrox, Favoxil, Movox);indalpine (Upstene); paroxetine (Paxil, Seroxat, Sereupin, Aropax,Deroxat, Divarius, Rexetin, Xetanor, Paroxat, Loxamine, Deparoc);sertraline (Zoloft, Lustral, Serlain, Asentra); vilazodone (Viibryd); orzimelidine (Zelmid, Normud).

8.30. Any of the foregoing methods wherein the patients is alsoreceiving a selective serotonin re-uptake inhibitor, e.g. selected fromone or more of citalopram (Celexa, Cipramil, Cipram, Dalsan, Recital,Emocal, Sepram, Seropram, Citox, Cital); dapoxetine (Priligy);escitalopram (Lexapro, Cipralex, Seroplex, Esertia); fluoxetine (Depex,Prozac, Fontex, Seromex, Seronil, Sarafem, Ladose, Motivest, Flutop,Fluctin (EUR), Fluox (NZ), Depress (UZB), Lovan (AUS), Prodep (IND));fluvoxamine (Luvox, Fevarin, Faverin, Dumyrox, Favoxil, Movox);indalpine (Upstene); paroxetine (Paxil, Seroxat, Sereupin, Aropax,Deroxat, Divarius, Rexetin, Xetanor, Paroxat, Loxamine, Deparoc);sertraline (Zoloft, Lustral, Serlain, Asentra); vilazodone (Viibryd); orzimelidine (Zelmid, Normud).

In still another preferred embodiment of the eighth aspect, theinvention provides Method I or any of 8.1-8.30, wherein the Compounds orCompositions of the Invention as hereinbefore described are administeredfor controlled- and/or sustained-release of the active compounds of theinvention over a period of from about 7 days, about 14 days, about 30 toabout 180 days, preferably over the period of about 30, about 60 orabout 90 days. Controlled- and/or sustained-release is particularlyuseful for circumventing premature discontinuation of therapy,particularly for antipsychotic drug therapy where non-compliance ornon-adherence to medication regimes is a common occurrence.

In another embodiment of the eighth aspect, the invention providesmethods for the prophylaxis or treatment of one or more disordersassociated with dementia, e.g., disorders associated with mild cognitionimpairment and dementing illnesses including senile dementia,Alzheimer's disease, Pick's disease, frontotemporal dementia,parasupranculear palsy, dementia with Lewy bodies and vascular dementiacomprising administering to a patient in need thereof, a therapeuticallyeffective amount of a compound as described in any of formulae 8.1-8.11(Method III).

In a further embodiment, the invention provides Method III as follows:

8.31. Method III, wherein the disorders associated with dementia aredisorders associated with mild cognition impairment and dementingillnesses including senile dementia, Alzheimer's disease, Pick'sdisease, frontotemporal dementia, parasupranculear palsy, dementia withLewy bodies and vascular dementia;

8.32. Method III or 8.31, wherein the disorders associated with dementiaare disorders associated with senile dementia, Alzheimer's disease,Pick's disease, frontotemporal dementia, parasupranculear palsy,dementia with Lewy bodies and vascular dementia;

8.33. Method III or 8.31, wherein the disorders associated with dementiaare disorders associated with Alzheimer's disease;

8.34. Method III or 8.31, wherein the disorders associated with dementiaare disorders associated with mild cognition impairment;

8.35. Method III or any of 8.31-8.34, wherein the disorder associateddementia to be treated is selected from the group consisting of (1)behavioral or mood disorders such as agitation/irritation,aggressive/assaultive behavior, anger, physical or emotional outbursts;(2) psychosis; (3) depression; and (4) sleep disorders in patientssuffering from dementia, particularly Alzheimer's disease;

8.36. Method III or any of 8.35-8.34, wherein the disorder to be treatedis psychosis in a patient with dementia, particularly Alzheimer'sdisease;

8.37. Method III or any of 8.35-8.34, wherein the disorder to be treatedis depression in a patient with dementia, particularly Alzheimer'sdisease;

8.38. Method III or any of 8.35-8.34, wherein the dosage of the Compoundof the invention is 10-100 mg, in free or pharmaceutically acceptablesalt, non-prodrug form, per day;

8.39. Method III or any of the formulae above, wherein the disorder tobe treated is behavioral or mood disorders such as agitation/irritation,aggressive/assaultive behavior, anger, physical or emotional outburstsin a patient with dementia, particularly Alzheimer's disease;

8.40. Method III or any of the formulae above, wherein the disorder tobe treated is sleep disorders in a patient with dementia, particularlyAlzheimer's disease;

8.41. Method III or any of the formulae above, wherein the disorder tobe treated is sleep maintenance insomnia, frequent awakenings, andwaking up feeling unrefreshed in a patient with dementia, particularlyAlzheimer's disease;

8.42. Method III or any of the formulae above, wherein the disorder tobe treated is sleep maintenance insomnia in a patient with dementia,particularly Alzheimer's disease;

8.43. Method III or any of the formulae above, wherein the disorder tobe treated is advanced sleep-phase syndrome in a patient with dementia,particularly Alzheimer's disease;

8.44. Method III or any of the formulae above, wherein the disorder tobe treated is delayed sleep-phase syndrome in a patient with dementia,particularly Alzheimer's disease;

8.45. Method III or any of the formulae above, wherein the dosage of theCompound of the invention is 1-10 mg per day;

8.46. Method III or any of the formulae above, further comprisesadministering one or more therapeutic agents useful for the prophylaxisor treatment of dementia, particularly Alzheimer's disease;

8.47. Method III or any of the formulae above, wherein the therapeuticagent useful for the prophylaxis or treatment of dementia, particularlyAlzheimer's disease is a cholinesterase inhibitor (e.g.,acetylcholinesterase inhibitor) or an N-Methyl D-Asparate (NMDA)receptor antagonist, in free or pharmaceutically acceptable salt form;

8.48. Method III or any of the formulae above, wherein thecholinesterase inhibitor (e.g., acetylcholinesterase inhibitor) isselected from the group consisting of Tacrine, rivastigmine (Exelon),donepezil (Aricept), and galantamine (Razadyne, formerly calledReminyl)) in free or pharmaceutically acceptable salt form;

8.49. Method III or any of the formulae above, wherein thecholinesterase inhibitor (e.g., acetylcholinesterase inhibitor) isdonepezil in free or pharmaceutically acceptable salt form;

8.50. Method III or any of the formulae above, wherein the NMDA receptorantagonist is memantine in free or pharmaceutically acceptable saltform;

8.51. Method III or any of the formulae above, wherein the therapeuticagent useful for the prophylaxis or treatment of dementia, particularlyAlzheimer's disease is a combination of a cholinesterase inhibitor(e.g., acetylcholinesterase inhibitor) and an N-Methyl D-Asparate (NMDA)receptor antagonist;

8.52. Method III or any of the formulae above, wherein the one or moretherapeutic agent(s) useful for the prophylaxis or treatment ofdementia, particularly Alzheimer's disease or symptoms thereof is acombination of donepezil and memantine in free or pharmaceuticallyacceptable salt form.

In the ninth aspect, the invention provides a method (Method II) for theprophylaxis or treatment one or more sleep disorders comprisingadministering to a patient in need thereof an effective amount of acompound as described in the following formulae:

9.1 a compound of Formula I, I(a), I(b) or any of formulae 1.1-1.37 ashereinbefore described;

9.2 a compound of Formula II, II(a), II(b) or any of formulae 2.1-2.31,in free or pharmaceutically acceptable salt form as hereinbeforedescribed;

9.3 a compound of Formula III or any of formulae 3.1-3.19 ashereinbefore described;

9.4 a compound of Formula IV or any of formulae 4.1-4.4 as hereinbeforedescribed, in free or pharmaceutically acceptable salt form;

9.5 a Pharmaceutical Composition as described in formula 5.1;

9.6 a Pharmaceutical Composition as described in formula 5.2;

9.7 a Pharmaceutical Composition as described in formula 5.3;

9.8 a Pharmaceutical Composition as described in formula 5.4;

9.9 a Pharmaceutical Composition as described in formula 5.5;

9.10 a Pharmaceutical Composition of any of formulae 6.1-6.5; or

9.11 Composition of any of formulae P.1-P.7 as hereinbefore described;

In a further embodiment of the ninth aspect, the invention providesMethod II, 9.1-9.11, wherein the sleep disorder includes sleepmaintenance insomnia, frequent awakenings, and waking up feelingunrefreshed;

9.12 Any of the foregoing methods, wherein the sleep disorder is sleepmaintenance insomnia;

9.13 Any of the foregoing methods, wherein the effective amount is 1mg-10 mg, e.g., 1 mg-5 mg, preferably 2.5-5 mg, in free orpharmaceutically acceptable salt, non-prodrug form, per day;

9.14 Any of the foregoing methods, wherein the effective amount is 2.5mg or 5 mg, in free or pharmaceutically acceptable salt, non-prodrugform, per day;

9.15 Any of the foregoing methods wherein the sleep disorder is in apatient suffering from or at risk of dyskinesia, e.g., a patientreceiving dopaminergic medications, e.g., selected from levodopa andlevodopa adjuncts (carbidopa, COMT inhibitors, MAO-B inhibitors),dopamine agonists, and anticholinergics, e.g., receiving levodopa;

9.16 Any of the foregoing methods wherein the patient suffers fromParkinson's disease.

The compound of Formula Q as hereinbefore described and the compounds ofthe Invention, upon conversion to the compound of Formula Q, or theactive compounds as hereinbefore described, provides effective treatmentof 5-HT2A, SERT and/or D₂ receptor related disorders without or withminimal extrapyramidal side effects as similarly disclosed and claimedin WO 2009/145900, the contents of which are incorporated by referencein their entirety. Therefore, the compounds of the Invention, thePharmaceutical Compositions of the Invention or the Depot formulation(Compositions of any of formulae 5.1-5.5 or 6.1-6.5) may be used incombination with a second therapeutic agent, particularly at lowerdosages than when the individual agents are used as a monotherapy so asto enhance the therapeutic activities of the combined agents withoutcausing the undesirable side effects commonly occur in conventionalmonotherapy. Therefore, the compounds of the Invention may besimultaneously, sequentially, or contemporaneously administered withother anti-depressant, anti-psychotic, other hypnotic agents, and/oragents use to treat Parkinson's disease or mood disorders. In anotherexample, side effects may be reduced or minimized by administering aneffective amount of a compound of the Invention in combination with oneor more second therapeutic agents in free or salt form, wherein thedosages of (i) the second therapeutic agent(s) or (ii) both compound ofthe Invention and the second therapeutic agents, are lower than if theagents/compounds are administered as a monotherapy. In a particularembodiment, the compounds of the Invention are useful to treatdyskinesia in a patient receiving dopaminergic medications, e.g.,selected from levodopa and levodopa adjuncts (carbidopa, COMTinhibitors, MAO-B inhibitors), dopamine agonists, and anticholinergics,e.g., such as are used in the treatment of Parkinson's disease.

Therefore, in the tenth aspect, the current invention provides Method Ior III, e.g., or any of formulae 8.1-8.52, or Method II or any of9.1-9.16, further comprises one or more therapeutic agents selected fromcompounds that modulate GABA activity (e.g., enhances the activity andfacilitates GABA transmission), a GABA-B agonist, a 5-HT modulator(e.g., a 5-HTIa agonist, a 5- HT_(2A) antagonist, a 5-HT2a inverseagonist, etc.), a melatonin agonist, an ion channel modulator (e.g.,blocker) , a serotonin-2 antagonist/reuptake inhibitor (SARIs), anorexin receptor antagonist, an H3 agonist or antagonist, a noradrenergicagonist or antagonist, a galanin agonist, a CRH antagonist, human growthhormone, a growth hormone agonist, estrogen, an estrogen agonist, aneurokinin- 1 drug, an anti-depressant, and an antipsychotic agent,e.g., an atypical antipsychotic agent, in free or pharmaceuticallyacceptable salt form (Method I-A, II-A, III-A, respectively).

In a further embodiment of the tenth aspect, the invention providesMethod I-A, II-A or III-A as follows, further comprising one or moretherapeutic agents.

10.1 Method I-A, II-A or III-A, wherein the therapeutic agent(s) iscompounds that modulate GABA activity (e.g., enhances the activity andfacilitates GABA transmission);

10.2 Method I-A, II-A or III-A or 10.1, wherein the GABA compound isselected from a group consisting of one or more of doxepin, alprazolam,bromazepam, clobazam, clonazepam, clorazepate, diazepam, flunitrazepam,fiurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazapam,triazolam, indiplon, zopiclone, eszopiclone, zaleplon, Zolpidem,gabaxadol, vigabatrin, tiagabine, EVT 201 (Evotec Pharmaceuticals) andestazolam;

10.3 Method I-A, II-A or III-A, wherein the therapeutic agent is anadditional 5HT2a antagonist;

10.4 Method I-A, II-A or III-A or 10.3, wherein said additional 5HT2aantagonist is selected from one or more of ketanserin, risperidone,eplivanserin, volinanserin (Sanofi-Aventis, France), pruvanserin, MDL100907 (Sanofi-Aventis, France), HY 10275 (Eli Lilly), APD 125 (ArenaPharmaceuticals, San Diego, Calif.), and AVE8488 (Sanofi-Aventis,France);

10.5 Method I-A, II-A or III-A, wherein the therapeutic agent is amelatonin agonist;

10.6 Method I-A, II-A or III-A or 10.5, wherein the melatonin agonist isselected from a group consisting of one or more of melatonin, ramelteon(ROZEREM®, Takeda Pharmaceuticals, Japan), VEC- 162 (VandaPharmaceuticals, Rockville, Md.), PD-6735 (Phase II Discovery) andagomelatine;

10.7 Method I-A, II-A or III-A, wherein the therapeutic agent is an ionchannel blocker;

10.8 Method I-A, II-A or III-A or 10.7, wherein said ion channel blockeris one or more of lamotrigine, gabapentin and pregabalin.

10.9 Method I-A, II-A or III-A, wherein the therapeutic agent is anorexin receptor antagonist;

10.10 Method I-A, II-A or III-A or 10.9, wherein the orexin receptorantagonist is selected from a group consisting of orexin, a1,3-biarylurea, SB-334867-a (GlaxoSmithKline, UK), GW649868(GlaxoSmithKline) and a benzamide derivative;

10.11 Method I-A, II-A or III-A, wherein the therapeutic agent is theserotonin-2 antagonist/reuptake inhibitor (SARI);

10.12 Method I-A, II-A or III-A or 10.11, wherein the serotonin-2antagonist/reuptake inhibitor (SARI) is selected from a group consistingof one or more Org 50081 (Organon-Netherlands), ritanserin, nefazodone,serzone and trazodone;

10.13 Method I-A, II-A or III-A, wherein the therapeutic agent is the5HT1a agonist;

10.14 Method I-A, II-A or III-A or 10.13, wherein the 5HT1a agonist isselected from a group consisting of one or more of repinotan, sarizotan,eptapirone, buspirone and MN-305 (MediciNova, San Diego, CA);

10.15 Method I-A, II-A or III-A, wherein the therapeutic agent is theneurokinin-1 drug;

10.16 Method I-A, II-A or III-A or 10.15, wherein the neurokinin-1 drugis Casopitant (GlaxoSmithKline);

10.17 Method I-A, II-A or III-A, wherein the therapeutic agent is anantipsychotic agent;

10.18 Method I-A, II-A or III-A or 10.17, wherein the antipsychoticagent is selected from a group consisting of chlorpromazine,haloperidol, droperidol, fluphenazine, loxapine, mesoridazine molidone,perphenazine, pimozide, prochlorperazine promazine, thioridazine,thiothixene, trifluoperazine, clozapine, aripiparazole, olanzapine,quetiapine, risperidone, ziprasidone and paliperidone;

10.19 Method I-A, II-A or III-A, wherein the therapeutic agent is ananti-depressant;

10.20 Method I-A, II-A or III-A or 10.19, wherein the anti-depressant isselected from amitriptyline, amoxapine, bupropion, citalopram,clomipramine, desipramine, doxepin, duloxetine, escitaloprame,fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline,mirtazapine, nefazodone, nortriptyline, paroxetine, phenlzine sulfate,protiptyline, sertraline, tranylcypromine, trazodone, trimipramine, andvelafaxine;

10.21 Method I-A, II-A or III-A, 10.17 or 10.18, wherein theantipsychotic agent is an atypical antipsychotic agent;

10.22 Method I-A, II-A or III-A, or any of 10.17-10.21, wherein theatypical antipsychotic agent is selected from a group consisting ofclozapine, aripiparazole, olanzapine, quetiapine, risperidone,ziprasidone, and paliperidone;

10.23 Method I-A, II-A or III-A, wherein the therapeutic agent isselected from any of methods 10.1-10.22, e.g., selected from a groupconsisting of modafinil, armodafinil, doxepin, alprazolam, bromazepam,clobazam, clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam,lorazepam, midazolam, nitrazepam, oxazepam, temazapam, triazolam,indiplon, zopiclone, eszopiclone, zaleplon, Zolpidem, gabaxadol,vigabatrin, tiagabine, EVT 201 (Evotec Pharmaceuticals), estazolam,ketanserin, risperidone, eplivanserin, volinanserin (Sanofi-Aventis,France), pruvanserin, MDL 100907 (Sanofi-Aventis, France), HY 10275 (EliLilly), APD 125 (Arena Pharmaceuticals, San Diego, Calif.), AVE8488(Sanofi-Aventis, France), repinotan, sarizotan, eptapirone, buspirone,MN-305 (MediciNova, San Diego, Calif.), melatonin, ramelteon (ROZEREM®,Takeda Pharmaceuticals, Japan), VEC-162 (Vanda Pharmaceuticals,Rockville, Md.), PD-6735 (Phase II Discovery), agomelatine, lamotrigine,gabapentin, pregabalin, orexin, a 1,3-biarylurea, SB-334867-a(GlaxoSmithKline, UK), GW649868 (GlaxoSmithKline), a benzamidederivative, Org 50081 (Organon-Netherlands), ritanserin, nefazodone,serzone, trazodone, Casopitant (GlaxoSmithKline), amitriptyline,amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin,duloxetine, escitaloprame, fluoxetine, fluvoxamine, imipramine,isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline,paroxetine, phenlzine sulfate, protiptyline, sertraline,tranylcypromine, trazodone, trimipramine, velafaxine, chlorpromazine,haloperidol, droperidol, fluphenazine, loxapine, mesoridazine molidone,perphenazine, pimozide, prochlorperazine promazine, thioridazine,thiothixene, trifluoperazine, clozapine, aripiparazole, olanzapine,quetiapine, risperidone, ziprasidone and paliperidone;

10.24 Method I-A, II-A or III-A wherein the therapeutic agent is an H3agonist;

10.25 Method I-A, II-A or III-A, wherein the therapeutic agent is an H3antagonist;

10.26 Method I-A, II-A or III-A, wherein the therapeutic agent is anoradrenergic agonist or antagonist;

10.27 Method I-A, II-A or III-A, wherein the therapeutic agent is agalanin agonist;

10.28 Method I-A, II-A or III-A, wherein the therapeutic agent is a CRHantagonist;

10.29 Method I-A, II-A or III-A, wherein the therapeutic agent is ahuman growth hormone;

10.30 Method I-A, II-A or III-A, wherein the therapeutic agent is agrowth hormone agonist;

10.31 Method I-A, II-A or III-A, wherein the therapeutic agent isestrogen;

10.32 Method I-A, II-A or III-A, wherein the therapeutic agent is anestrogen agonist;

10.33 Method I-A, II-A or III-A, wherein the therapeutic agent is aneurokinin-1 drug;

10.34 Method I-A, II-A or III-A, wherein a therapeutic agent is combinedwith compounds of Formula (I) and the therapeutic agent is ananti-Parkinson agent such as L-dopa, co-careldopa, duodopa, stalova,Symmetrel, benzotropine, biperiden, bromocryiptine, entacapone,pergolide, pramipexole, procyclidine, ropinirole, selegiline andtolcapone;

10.35 Method I-A, II-A or III-A, wherein compounds of the invention maybe used to treat sleep disorders, depression, pyschosis, or anycombinations thereof, in patients suffering from the listed diseasesand/or Parkinson's disease;

10.36 Method I-A, II-A or III-A, wherein the disorder is selected fromat least one or more of psychosis, e.g., schizophrenia, depression, mooddisorders, sleep disorders (e.g., sleep maintenance and/or sleep onset)or any combination of disorders thereof;

10.37 Any of the foregoing methods wherein the disorder is sleepdisorder;

10.38 Any of the foregoing methods, wherein the disorder is sleepdisorder associated with psychosis, e.g., schizophrenia or Parkinson'sdisease; in free or pharmaceutically acceptable salt form.

In the eleventh aspect of the invention, the combination of a compoundof the Invention and one or more second therapeutic agents as describedin Method I-A, II-A or III-A or any of 10.1-10.38, may be administeredas a Pharmaceutical Composition or a Depot Composition as hereinbeforedescribed. The combination compositions can include mixtures of thecombined drugs, as well as two or more separate compositions of thedrugs, which individual compositions can be, for example,co-administered together to a patient.

In a particular embodiment, Method I-A, II-A or III-A, or any of10.1-10.38 comprises administering to a patient in need thereof, aneffective amount a compound of the Invention in combination with anatypical antipsychotic agent, e.g., a compound selected from clozapine,aripiparazole, olanzapine, quetiapine, risperidone, ziprasidone, orpaliperidone, in free or pharmaceutically acceptable salt form, forexample wherein the dosage of the atypical antipsychotic agent isreduced and/or side effects are reduced.

In another embodiment, Method I-A, II-A or III-A, or any of 10.1-10.38comprises administering to a patient in need thereof, an effectiveamount of a compound of the Invention in combination with ananti-depressant, e.g., amitriptyline, amoxapine, bupropion, citalopram,clomipramine, desipramine, doxepin, duloxetine, escitaloprame,fluoxetine, fiuvoxamine, imipramine, isocarboxazid, maprotiline,mirtazapine, nefazodone, nortriptyline, paroxetine, phenlzine sulfate,protiptyline, sertraline, tranylcypromine, trazodone, trimipramine, orvelafaxine, in free or pharmaceutically acceptable salt form.Alternatively, the anti-depressant may be used as an adjunct medicationin addition to the compound of the Invention.

In still another embodiment, Method I-A, II-A or III-A or any of10.1-10.38 comprises administering to a patient in need thereof, aneffective amount of a compound of the Invention in combination with acompound that modulates GABA activity, e.g., a compound selected fromdoxepin, alprazolam, bromazepam, clobazam, clonazepam, clorazepate,diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam,oxazepam, temazapam, triazolam, indiplon, zopiclone, eszopiclone,zaleplon, Zolpidem, gabaxadol, vigabatrin, tiagabine, EVT 201 (EvotecPharmaceuticals), estazolam or any combinations thereof, in free orpharmaceutically acceptable salt form.

In another preferred embodiment, Method I-A, II-A or III-A or any of10.1-10.38 comprises administering to a patient in need thereof, aneffective amount of a compound of the Invention in combination withdoxepin in free or pharmaceutically acceptable salt form. Dosages ofdoxepin can vary in any range known to a person of ordinary skill in theart. In one example, a 10 mg dose of doxepin may be combined with anydosage of a compound of the Invention.

In another embodiment, Method I-A, II-A or III-A or any of 10.1-10.38comprises administering to a patient in need thereof, an effectiveamount of a compound of the Invention in combination (including as partof a daily dosage regimen) with an atypical stimulant, e.g., amodafinil, adrafinil, or armodafinil. A regimen incorporating a compoundof the Invention with such drugs promotes more regular sleep, and avoidsside effects such as psychosis or mania associated with higher levels ofsuch drugs, e.g., in the treatment of bipolar depression, cognitionassociated with schizophrenia, and excessive sleepiness and fatigue inconditions such as Parkinson's disease and cancer.

In the twelfth aspect, the invention provides use of a compound asdescribed in the following formulae:

12.1 a compound of Formula I, I(a), I(b) or any of formulae 1.1-1.38 ashereinbefore described;

12.2 a compound of Formula II, II(a), II(b) or any of formulae 2.1-2.31,in free or pharmaceutically acceptable salt form as hereinbeforedescribed;

12.3 a compound of Formula III or any of formulae 3.1-3.19 ashereinbefore described;

12.4 a compound of Formula IV or any of formulae 4.1-4.4 as hereinbeforedescribed, in free or pharmaceutically acceptable salt form;

12.5 a Pharmaceutical Composition as described in formula 5.1;

12.6 a Pharmaceutical Composition as described in formula 5.2;

12.7 a Pharmaceutical Composition as described in formula 5.3;

12.8 a Pharmaceutical Composition as described in formula 5.4;

12.9 a Pharmaceutical Composition as described in formula 5.5;

12.10 a Depot Composition of any of formulae 6.1-6.5; or

12.11 Composition of any of formulae P.1-P.7 as hereinbefore described;(in the manufacture of a medicament) for the treatment or prophylaxis ofone or more disorders as disclosed hereinbefore, e.g., in any of MethodI or III, any of 8.1-8.52, Method II, any of 9.1-9.16, Methods I-A, II-Aor III-A, any of 10.1-10.38.

In the thirteenth aspect, the invention provides a pharmaceuticalcomposition as hereinbefore described for use in the treatment orprophylaxis of one or more disorders as disclosed hereinbefore, e.g., inany of Method I or III, any of 8.1-8.52, Method II, any of 9.1-9.16,Methods I-A, II-A or III-A, any of 10.1-10.38, or any methods describedin the eleventh or twelfth aspect of the invention.

DETAILED DESCRIPTION OF THE INVENTION

If not otherwise specified or clear from context, the following terms asused herein have the following meetings:

a. “Alkyl” as used herein is a saturated or unsaturated hydrocarbonmoiety, e.g., one to twenty-four carbon atoms in length, which may belinear or branched (e.g., n-butyl or tert-butyl), preferably linear,saturated or unsaturated unless otherwise specified. For example, “C₁₋₂₄alkyl” denotes alkyl having 1 to 24 carbon atoms. In one embodiment,alkyl is optionally substituted with one or more hydroxy or C₁₋₂₂alkoxy(e.g., ethoxy) groups. In another embodiment, alkyl contains 1 to 24carbon atoms, preferably straight chain and optionally saturated orunsaturated, for example R₁ is an alkyl chain containing 1 to 24 carbonatoms, e.g., 6-15 carbon atoms, 16-24 carbon atoms, e.g., so thattogether with the —C(O)— to which it attaches, e.g., when cleaved fromthe compound, forms the residue of a natural or unnatural, saturated orunsaturated fatty acid. In still another embodiment, alkyl contains 1 to6 carbon atoms.

Unless otherwise indicated, the compounds of the Invention includes thecompounds of Formula I, I(a), I(b) or any of formulae 1.1-1.38 ashereinbefore described, Formula II, II(a), II(b) or any of formulae2.1-2.31, in free or pharmaceutically acceptable salt form; or acompound of Formula III or any of formulae 3.1-3.19 as hereinbeforedescribed; and a compound of Formula IV or any of formulae 4.1-4.4 ashereinbefore described, in free or pharmaceutically acceptable saltform. In certain embodiment, e.g., depot formulation, the compound ofFormula Q is also included in the compounds of the invention.

The compounds of Formula II, II(a), II(b) or any of formulae 2.1-2.31and the compounds of Formula IV or any of formulae 4.1-4.4 ashereinbefore described, may exist in free or salt, e.g., as acidaddition salt, form. An acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulphuric, phosphoric, acid acetic,trifluoroacetic, citric, maleic acid, toluene sulfonic, propionic,succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,pamoic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,ethane disulfonic, oxalic, isethionic acid, and the like. In addition asalt of a compound of the invention which is sufficiently acidic is analkali metal salt, for example a sodium or potassium salt, an alkalineearth metal salt, for example a calcium or magnesium salt, an ammoniumsalt or a salt with an organic base which affords aphysiologically-acceptable cation, for example a salt with methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)-amine. In a particular embodiment, the salt of thecompounds of the Invention is a toluenesulfonic acid addition salt. Inanother particular embodiment, the salt of the compounds of theInvention is a fumeric acid addition salt. In a particular embodiment,the salt of the compounds of the Invention is a phosphoric acid additionsalt.

The compounds of the Invention are intended for use as pharmaceuticals,therefore pharmaceutically acceptable salts are preferred. Salts whichare unsuitable for pharmaceutical uses may be useful, for example, forthe isolation or purification of free compounds of the Invention, andare therefore also included.

The compounds of the Invention may comprise one or more chiral carbonatoms. The compounds thus exist in individual isomeric, e.g.,enantiomeric or diasteriomeric form or as mixtures of individual forms,e.g., racemic/diastereomeric mixtures. Any isomer may be present inwhich the asymmetric center is in the (R)-, (S)-, or (R, S)-configuration. The invention is to be understood as embracing bothindividual optically active isomers as well as mixtures (e.g.,racemic/diasteromeric mixtures) thereof. Accordingly, the compounds ofthe Invention may be a racemic mixture or it may be predominantly, e.g.,in pure, or substantially pure, isomeric form, e.g., greater than 70%enantiomeric/diastereomeric excess (“ee”), preferably greater than 80%ee, more preferably greater than 90% ee, most preferably greater than95% ee. The purification of said isomers and the separation of saidisomeric mixtures may be accomplished by standard techniques known inthe art (e.g., column chromatography, preparative TLC, preparative HPLC,simulated moving bed and the like).

Geometric isomers by nature of substituents about a double bond or aring may be present in cis (Z) or trans (E) form, and both isomericforms are encompassed within the scope of this invention.

The Compounds of the Invention exist in prodrug form. The term “prodrug”is an art recognized term and refers to a drug precursor prior toadministration, but generates or releases the active metabolite in vivofollowing administration, via some chemical or physiological process.For example, the compounds of Formula I et seq. will be cleaved torelease the active compound:

wherein X is —N(H)—, —N(C₁₋₆alkyl)— or —O—; Y is —C(O)—, —O— or—C(H)(OR⁴)—; and R⁴ is H. The compounds of Formula II et seq. will becleaved to release the active compound:

wherein X is —N(H)—; Y is —C(O)—, —O— or —C(H)(OR⁴)—; and R⁴ is H. Thecompounds of Formula III et seq. will be cleaved to release the activecompound:

wherein X is —N(H)—, —N(C₁₋₄alkyl)— or —O—; R¹ is H or C₁₋₆alkyl (e.g.,methyl); and R² is H or OR³ wherein R³ is H, provided that R¹ and R² arenot both H, and R¹ and R³ are not both H. The compounds of Formula IV etseq. will be cleaved to release the active compound:

wherein R¹ is H or C₁₋₆alkyl (e.g., methyl); R² is H or OR³ wherein R³is H; provided that R¹ and R² are not both H, and R¹ and R³ are not bothH.

The prodrug compounds of the Invention are particularly useful forsustained-and/or delayed release so as to achieve a long acting effect,e.g., wherein the active compounds as hereinbefore described or theactive compound of Formula Q are released over a period of from about 7to about 14 to about 30 to about 180 days, preferably over about 30 orabout 60 or about 90 days, for example as described in any of formulae6.1-6.5 or 5.1-5.5 which comprises a viscosity enhancing agent asdiscussed above. Preferably, the sustained and/or delayed-releaseformulation is an injectable formulation.

Alternatively and/or additionally, the compounds of the Invention andthe Compound of Formula Q may be included as a depot formulation, e.g.,by dispersing, dissolving or encapsulating the compounds of theInvention in a polymeric matrix as described in any of composition6.1-6.5, such that the compound is continually released as the polymerdegrades over time. The release of the compounds of the Invention or theCompound of Formula Q from the polymeric matrix provides for thecontrolled- and/or delayed- and/or sustained-release of the compounds,e.g., from the pharmaceutical depot composition, into a subject, forexample a warm-blooded animal such as man, to which the pharmaceuticaldepot is administered. Thus, the pharmaceutical depot delivers theactive compounds described hereinbefore or the Compound of Formula Q tothe subject at concentrations effective for treatment of the particulardisease or medical condition over a sustained period of time, e.g.,7-180 days, preferably about 7 or about 14 or about 30, about 60 orabout 90 days.

Polymers useful for the polymeric matrix in the Composition of theInvention (e.g., Depot composition of any of Formulae 6.1-6.5) mayinclude a polyester of a hydroxyfatty acid and derivatives thereof orother agents such as polylactic acid, polyglycolic acid, polycitricacid, polymalic acid, poly-beta.-hydroxybutyric acid,epsilon.-capro-lactone ring opening polymer, lactic acid-glycolic acidcopolymer, 2-hydroxybutyric acid-glycolic acid copolymer, polylacticacid-polyethyleneglycol copolymer or polyglycolicacid-polyethyleneglycol copolymer), a polymer of an alkylalpha-cyanoacrylate (for example poly(butyl 2-cyanoacrylate)), apolyalkylene oxalate (for example polytrimethylene oxalate orpolytetramethylene oxalate), a polyortho ester, a polycarbonate (forexample polyethylene carbonate or polyethylenepropylene carbonate), apolyortho-carbonate, a polyamino acid (for examplepoly-gamma.-L-alanine, poly-.gamma.-benzyl-L-glutamic acid orpoly-y-methyl-L-glutamic acid), a hyaluronic acid ester, and the like,and one or more of these polymers can be used.

If the polymers are copolymers, they may be any of random, block and/orgraft copolymers. When the above alpha-hydroxycarboxylic acids,hydroxydicarboxylic acids and hydroxytricarboxylic acids have opticalactivity in their molecules, any one of D-isomers, L-isomers and/orDL-isomers may be used. Among others, alpha-hydroxycarboxylic acidpolymer (preferably lactic acid-glycolic acid polymer), its ester,poly-alpha-cyanoacrylic acid esters, etc. may be used, and lacticacid-glycolic acid copolymer (also referred to aspoly(lactide-alpha-glycolide) or poly(lactic-co-glycolic acid), andhereinafter referred to as PLGA) are preferred. Thus, in one aspect thepolymer useful for the polymeric matrix is PLGA. As used herein, theterm PLGA includes polymers of lactic acid (also referred to aspolylactide, poly(lactic acid), or PLA). Most preferably, the polymer isthe biodegradable poly(d,l-lactide-co-glycolide) polymer.

In a preferred embodiment, the polymeric matrix of the invention is abiocompatible and biodegradable polymeric material. The term“biocompatible” is defined as a polymeric material that is not toxic, isnot carcinogenic, and does not significantly induce inflammation in bodytissues. The matrix material should be biodegradable wherein thepolymeric material should degrade by bodily processes to productsreadily disposable by the body and should not accumulate in the body.The products of the biodegradation should also be biocompatible with thebody in that the polymeric matrix is biocompatible with the body.Particular useful examples of polymeric matrix materials includepoly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid,copolymers of the foregoing, poly(aliphatic carboxylic acids),copolyoxalates, polycaprolactone, polydioxonone, poly(ortho carbonates),poly(acetals), poly(lactic acid-caprolactone), polyorthoesters,poly(glycolic acid-caprolactone), polyanhydrides, and natural polymersincluding albumin, casein, and waxes, such as, glycerol mono- anddistearate, and the like. The preferred polymer for use in the practiceof this invention is dl(polylactide-co-glycolide). It is preferred thatthe molar ratio of lactide to glycolide in such a copolymer be in therange of from about 75:25 to 50:50.

Useful PLGA polymers may have a weight-average molecular weight of fromabout 5,000 to 500,000 daltons, preferably about 150,000 daltons.Dependent on the rate of degradation to be achieved, different molecularweight of polymers may be used. For a diffusional mechanism of drugrelease, the polymer should remain intact until all of the drug isreleased from the polymeric matrix and then degrade. The drug can alsobe released from the polymeric matrix as the polymeric excipientbioerodes.

The PLGA may be prepared by any conventional method, or may becommercially available. For example, PLGA can be produced byring-opening polymerisation with a suitable catalyst from cycliclactide, glycolide, etc. (see EP-0058481B2; Effects of polymerizationvariables on PLGA properties: molecular weight, composition and chainstructure).

It is believed that PLGA is biodegradable by means of the degradation ofthe entire solid polymer composition, due to the break-down ofhydrolysable and enzymatically cleavable ester linkages under biologicalconditions (for example in the presence of water and biological enzymesfound in tissues of warm-blooded animals such as humans) to form lacticacid and glycolic acid. Both lactic acid and glycolic acid arewater-soluble, non-toxic products of normal metabolism, which mayfurther biodegrade to form carbon dioxide and water. In other words,PLGA is believed to degrade by means of hydrolysis of its ester groupsin the presence of water, for example in the body of a warm-bloodedanimal such as man, to produce lactic acid and glycolic acid and createthe acidic microclimate. Lactic and glycolic acid are by-products ofvarious metabolic pathways in the body of a warm-blooded animal such asman under normal physiological conditions and therefore are welltolerated and produce minimal systemic toxicity.

In another embodiment, the polymeric matrix useful for the invention maycomprise a star polymer wherein the structure of the polyester isstar-shaped. These polyesters have a single polyol residue as a centralmoiety surrounded by acid residue chains. The polyol moiety may be, e.g., glucose or, e. g., mannitol. These esters are known and described inGB 2,145,422 and in U.S. Pat. No. 5,538,739, the contents of which areincorporated by reference.

The star polymers may be prepared using polyhydroxy compounds, e. g.,polyol, e. g., glucose or mannitol as the initiator. The polyol containsat least 3 hydroxy groups and has a molecular weight of up to about20,000 Daltons, with at least 1, preferably at least 2, e. g. , as amean 3 of the hydroxy groups of the polyol being in the form of estergroups, which contain polylactide or co-polylactide chains. The branchedpolyesters, e. g., poly (d, l-lactide-co-glycolide) have a centralglucose moiety having rays of linear polylactide chains.

The depot composition of the invention (e.g., compositions of any offormulae 6.1-6.5) as hereinbefore described may comprise the polymer inthe form of microparticles or nanoparticles, or in a liquid form, withthe compounds of the Invention dispersed or encapsulated therein.“Microparticles” is meant solid particles that contain the compounds ofthe Invention either in solution or in solid form wherein such compoundis dispersed or dissolved within the polymer that serves as the matrixof the particle. By an appropriate selection of polymeric materials, amicroparticle formulation can be made in which the resultingmicroparticles exhibit both diffusional release and biodegradationrelease properties.

When the polymer is in the form of microparticles, the microparticlesmay be prepared using any appropriate method, such as by a solventevaporation or solvent extraction method. For example, in the solventevaporation method, the compounds of the Invention and the polymer maybe dissolved in a volatile organic solvent (for example a ketone such asacetone, a halogenated hydrocarbon such as chloroform or methylenechloride, a halogenated aromatic hydrocarbon, a cyclic ether such asdioxane, an ester such as ethyl acetate, a nitrile such as acetonitrile,or an alcohol such as ethanol) and dispersed in an aqueous phasecontaining a suitable emulsion stabiliser (for example polyvinylalcohol, PVA). The organic solvent is then evaporated to providemicroparticles with the compounds of the Invention encapsulated therein.In the solvent extraction method, the compounds of the Invention andpolymer may be dissolved in a polar solvent (such as acetonitrile,dichloromethane, methanol, ethyl acetate or methyl formate) and thendispersed in an aqueous phase (such as a water/PVA solution). Anemulsion is produced to provide microparticles with the compounds of theInvention encapsulated therein. Spray drying is an alternativemanufacturing technique for preparing the microparticles.

Another method for preparing the microparticles of the invention is alsodescribed in both U.S. Pat. No. 4,389,330 and U.S. Pat. No. 4,530,840.

The microparticle of the present invention can be prepared by any methodcapable of producing microparticles in a size range acceptable for usein an injectable composition. One preferred method of preparation isthat described in U.S. Pat. No. 4,389,330. In this method the activeagent is dissolved or dispersed in an appropriate solvent. To theagent-containing medium is added the polymeric matrix material in anamount relative to the active ingredient that provides a product havingthe desired loading of active agent. Optionally, all of the ingredientsof the microparticle product can be blended in the solvent mediumtogether.

Solvents for the compounds of the Invention or the compound of Formula Qand the polymeric matrix material that can be employed in the practiceof the present invention include organic solvents, such as acetone;halogenated hydrocarbons, such as chloroform, methylene chloride, andthe like; aromatic hydrocarbon compounds; halogenated aromatichydrocarbon compounds; cyclic ethers; alcohols, such as, benzyl alcohol;ethyl acetate; and the like. In one embodiment, the solvent for use inthe practice of the present invention may be a mixture of benzyl alcoholand ethyl acetate. Further information for the preparation ofmicroparticles useful for the invention can be found in U.S. PatentPublication Number 2008/0069885, the contents of which are incorporatedherein by reference in their entirety.

The amount of the compounds of the Invention or the compounds of FormulaQ incorporated in the microparticles usually ranges from about 1 wt % toabout 90 wt. %, preferably 30 to 50 wt. %, more preferably 35 to 40 wt.%. By weight % is meant parts of the compounds of the Invention pertotal weight of microparticle.

The pharmaceutical depot may comprise a pharmaceutically-acceptablediluent or carrier, such as a water miscible diluent or carrier.

Details of Osmotic-controlled Release Oral delivery System compositionmay be found in EP 1 539 115 (U.S. Pub. No. 2009/0202631) and WO2000/35419, the contents of each of which are incorporated by referencein their entirety.

A “therapeutically effective amount” is any amount of the compounds ofthe invention (for example as contained in the pharmaceutical depot)which, when administered to a subject suffering from a disease ordisorder, is effective to cause a reduction, remission, or regression ofthe disease or disorder over the period of time as intended for thetreatment.

Dosages employed in practicing the present invention will of course varydepending, e.g. on the particular disease or condition to be treated,the particular compound of the Invention used, the mode ofadministration, and the therapy desired. Unless otherwise indicated, anamount of the compound of the Invention for administration (whetheradministered as a free base or as a salt form) refers to or is based onthe amount of the active drug compound in free base form or inpharmaceutically acceptable salt form (i.e., the calculation of theamount is based on the free base amount or pharmaceutically acceptablesalt amount and in a non-prodrug form). Therefore, the dosage is basedon the amount of the compound of Formula Q, wherein X is —N(CH₃)— and Yis —C(═O), in free base form and non-prodrug form (i.e., wherein theprodrug, e.g., substituent R⁵ of Formula II or the group—C(O)—O—C(R^(a))(R^(b))(R^(c)) or —C(R⁶)(R⁷)—O—C(O)-R⁸ on thequarternary ammonium nitrogen of Formula I, is cleaved off wherein X is—N(CH₃)— and Y is —C(═O)). In another embodiment, the dosage is based onthe amount of the compound of Formula Q, wherein X is —N(CH₃)-and Y is—C(═O), in pharmaceutically acceptable salt and non-prodrug form (i.e.,wherein the prodrug, e.g., substituent R⁵ of Formula II or the group—C(O)—O—C(R^(a))(R^(b))(R^(c)) or —C(R⁶)(R⁷)—O—C(O)—R⁸ on thequarternary ammonium nitrogen of Formula I, is cleaved off wherein X is—N(CH₃)— and Y is —C(═O)).

The compounds of the Invention may be administered by any satisfactoryroute, including orally, parenterally (intravenously, intramuscular orsubcutaneous) or transdermally, but are preferably administered orally.In certain embodiment, the compounds of the Invention, e.g., in depotformulation (e.g., formulae 5.1-5.5 or 6.1-6.5), is preferablyadministered parenterally, e.g., by injection.

In general, satisfactory results for Method I or III or any of formulae8.1-8.52 or use of the compounds of the Invention or the compounds ofFormula Q as hereinbefore described, e.g. for the treatment of acombination of diseases such as a combination of at least depression,psychosis, e.g., (1) psychosis, e.g., schizophrenia, in a patientsuffering from depression; (2) depression in a patient suffering frompsychosis, e.g., schizophrenia; (3) mood disorders associated withpsychosis, e.g., schizophrenia, or Parkinson's disease; and (4) sleepdisorders associated with psychosis, e.g., schizophrenia, or Parkinson'sdisease, as set forth above are indicated to be obtained on oraladministration at dosages of the order from about 1 mg to 100 mg oncedaily, preferably 2.5 mg-50 mg, e.g., 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg,40 mg or 50mg in free base or pharmaceutically acceptable, non-prodrugform, once daily, preferably via oral administration. Preferably, thedaily dosage is 20 mg-40 mg in free base or pharmaceutically acceptable,non-prodrug form. For example, the method of treating schizophrenia ordementia (e.g., in Methods I and III) comprises a daily dosage of 20-40mg in free base or pharmaceutically acceptable, non-prodrug form.

Satisfactory results for Method II or any of 9.1-9.15, or use of thecompounds of the Invention or compounds or Formula Q as hereinbeforedescribed, e.g. for the treatment of sleep disorder alone are indicatedto be obtained on oral administration at dosages of the order from about2.5 mg-5 mg, e.g., 2.5 mg, 3 mg, 4 mg or 5 mg, of a compound of theInvention, in free or pharmaceutically acceptable salt form, once daily,preferably via oral administration.

Satisfactory results for Method I-A or any of 10.1-10.38 are indicatedto be obtained at less than 100 mg, preferably less than 50 mg, e.g.,less than 40 mg, less than 30 mg, less than 20 mg, less than 10 mg, lessthan 5 mg, less than 2.5 mg in free base or pharmaceutically acceptable,non-prodrug form, once daily. Satisfactory results for Method II-A orany of 10.1-10.38 are indicated to be obtained at less than 5 mg,preferably less than 2.5 mg in free base or pharmaceutically acceptable,non-prodrug form.

For treatment of the disorders disclosed herein wherein the depotcomposition is used to achieve longer duration of action, the dosageswill be higher relative to the shorter action composition, e.g., higherthan 1-100 mg, e.g., 25 mg, 50 mg, 100 mg, 500 mg, 1,000 mg, or greaterthan 1000 mg in free base or pharmaceutically acceptable, non-prodrugform. For example, for the treatment of psychosis, schizophrenia ordementia (Methods I or III), the weekly biweekly and monthly dosages maybe about 100 mg-300 mg (e.g., 140 mg-160 mg), about 250 mg-600 mg (e.g.,280-300 mg) and about 500-1,240 mg (e.g., 600 mg-620 mg) of the compoundof the invention based on the free base or pharmaceutically acceptablesalt and non-prodrug form. Duration of action of the compounds of theInvention may be controlled by manipulation of the polymer composition,i.e., the polymer:drug ratio and microparticle size. Wherein thecomposition of the invention is a depot composition, administration byinjection is preferred.

The pharmaceutically acceptable salts of the compounds of the Inventioncan be synthesized from the parent compound which contains a basic oracidic moiety by conventional chemical methods. Generally, such saltscan be prepared by reacting the free base forms of these compounds witha stoichiometric amount of the appropriate acid in water or in anorganic solvent, or in a mixture of the two; generally, nonaqueous medialike ether, ethyl acetate, ethanol, isopropanol, or acetonitrile arepreferred. Further details for the preparation of these salts, e.g.,toluenesulfonic salt in amorphous or crystal form, may be found inPCT/US08/03340 and/or U.S. Provisional Appl. No. 61/036,069.

Pharmaceutical compositions comprising compounds of the Invention may beprepared using conventional diluents or excipients (an example include,but is not limited to sesame oil) and techniques known in the galenicart. Thus oral dosage forms may include tablets, capsules, solutions,suspensions and the like.

Methods of Making the Compounds of the Invention

The compounds of Formulae I, I(a), I(b) and 1.1-1.38 as hereinbeforedescribed may be prepared by reacting the compound of Formula A, whereinX and Y are defined in any of Formulae I, I(a), I(b) or 1.1-1.37:

with L-C(R⁶)(R⁷)—OC(O)—R⁸ wherein L is a leaving group such as halo,preferably iodo and R⁶, R⁷ and R⁸ are as defined in any of Formulae I,I(a), I(b) or 1.1-1.38, preferably R⁶ and R⁷ are H and R⁸ is C₉alkyl.L-C(R⁶)(R⁷)—OC(O)—R⁸, in turn, may be prepared by reacting Cl—C(O)—R⁸with zinc chloride and paraformaldehyde followed by reacting theresulting Cl—L-C(R⁶)(R⁷)—OC(O)—R⁸ with sodium iodide. R⁶, R⁷ and R⁸ areas defined in any of Formulae I, I(a), I(b) or 1.1-1.38, preferably R²and R³ are H and R¹ is C₉alkyl.

The compounds of Formulae II, II(a), II(b) and 2.1-2.31, in free orpharmaceutically acceptable salt form as hereinbefore described may beprepared by reacting the compound of Formula B:

wherein Y is as defined in any of Formulae II, II(a), II(b) or 2.1-2.31,with triphosgene and a base (e.g., pyridine) in a solvent such asdichloromethane. The resulting chloride-carbonyl derivative of Formula Bmay then be reacted with HO—C(R^(a))(R^(b))(R^(c)) to produce thecompounds of any of Formulae II, II(a), II(b) or 2.1-2.31, wherein R⁵ is—C(O)—O—C(R^(a))(R^(b))(R^(c)).

The compounds of Formulae II, II(a), II(b) and 2.1-2.31, wherein R⁵ is—C(R⁶)(R⁷)—O—C(O)—R⁸, in free or pharmaceutically acceptable salt formmay be prepared by reacting the compound of Formula B withL-C(R⁶)(R⁷)—OC(O)—R⁸ wherein L is a leaving group such as halo (e.g.,iodo) and R⁶, R⁷ and R⁸ are as defined in any of Formulae II, II(a),II(b) and 2.1-2.31.

The compounds of Formula A and Formula B may be prepared by methodsdisclosed in any of U.S. Pat. No. 8,309,722, WO 2011/133224, WO2008/112280; U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471;7,183,282; U.S. RE39680, and U.S. RE39679, the contents of each of whichare incorporated by reference in their entirety.

The compounds of Formula III and 3.1-3.19 wherein R² is —OR³ and R³ is Has hereinbefore described may be may be prepared by reacting Formula Cwith a Grignard reagent, R¹—MgX² wherein X² is halide, e.g., bromide orchloride, preferably bromide, R¹ and X are defined in Formula III, e.g.,R¹ is methyl and X is for example N(CH₃), e.g., in a solvent such astetrahydrofuran or diethyl ether, preferably tetrahydrofuran. Thereaction may be summarized in the reaction scheme below:

The Compound of Formula III, wherein R² is —OR³ wherein R³ is C₁₋₆alkylmay be prepared by reacting Formula D with R³—OH and BF₃.OH wherein R³is C₁₋₆alkyl. The reaction may be summarized in the reaction schemebelow:

The compounds of formulae III and IV may be prepared by using thecompounds of Formula D and Formula E wherein X, R¹ and R³ are as definedin any of Formulae III, and IV and the procedures described for FormulaI, I(a), I(b) and II, II(a) and II(b).

Isolation or purification of the disastereomers of the compounds of theInvention may be achieved by conventional methods known in the art,e.g., column purification, preparative thin layer chromatography,preparative HPLC, crystallization, trituration, simulated moving bedsand the like.

Salts of the compounds of the Invention such as Compounds of Formula IIand IV may be prepared as similarly described in U.S. Pat. Nos.6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; U.S. RE39680;U.S. RE39679; and WO 2009/114181, the contents of each of which areincorporated by reference in their entirety.

General Analytical UPLC Methods for the Determination of Compound Purity

Waters ACQUITY UPLC system: ACQUITY HSS T3 column, 50 mm×2.1 mm, 1.8 μm,25° C.; mobile phase A, 0.1% formic acid in water/acetonitrile (95/5);mobile phase B, 0.1% formic acid in acetonitrile; gradient, 0.0-3.0 min,5-95% B; 3.0-4.0 min, 95% B; 4.0-5.0 min, 95-5% B; flow rate 0.3 mL/min;detection at 210-400 nm.

General Preparative HPLC Methods for Compound Purification

All products are purified with a Waters semi-preparative HPLC system,which is equipped with a Delta 600EF pump and a 996 PDA detector.Column: Gemini, AXIA packed, 10 μm C18 110 Å, 250×21.2 mm; mobile phaseA, 0.1% formic acid in water; mobile phase B, acetonitrile; gradient isadjusted and optimized based on compound polarity; HPLC run time was 22min; flow rate was 23.8 mL/min; detection was at 210-350 nm.

EXAMPLE 1 Synthesis of(6bR,10aS)-8-Decanoyloxymethyl-8-[4-(4-fluoro-phenyl)-4-oxo-butyl]-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-iumformate

To a solution of decanoyl chloride (1.63 mL 4.2 mmol) andparaformaldehyde (126 mg) in acetone (6 mL) is added zinc chloride. Thereaction mixture is stirred at 65° C. overnight. Sodium iodide (1.9 g,12.6 mmol) is added into the reaction mixture, and the mixture isstirred at room temperature overnight. The reaction mixture is filteredand acetone is removed under reduced pressure. The residue is treatedwith hexanes, and then filtered. The filtrate is evaporated to drynessunder vacuum to give the crude iodomethyl decanoate, which is used inthe next step without further purification.

To a solution of the4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyridol[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluorophenyl)-butan-1-one(27 mg, 0.065 mmol) in methylene chloride (250 uL) is added the crudeiodomethyl decanoate (32 mg, 0.10 mmol). The reaction mixture is stirredat room temperature for 3 days, and then purified with asemi-preparative HPLC (Gemini column, AXIA packed, 10 mm C18 110 Å, 250

21.2 mm; mobile phase A, 0.1% formic acid in water; mobile phase B, 0.1%formic acid in acetonitrile; gradient is adjusted and optimized based oncompound polarity; run time 22 min; flow rate 24 mL/min; detection at210-350 nm) to give(6bR,10aS)-8-Decanoyloxymethyl-8-[4-(4-fluoro-phenyl)-4-oxo-butyl]-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-iumformate. ESI-MS (m/z, positive mode): 578.4.

Alternatively, the compound of Example 1 may be prepared as follows: Toa solution of the4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluorophenyl)-butan-1-one(50.8 mg, 0.13 mmol) in acetonitrile (2.5 mL) is added chloromethyldecanoate (32.7 mg, 0.14 mmol), followed by adding NaI (61 mg, 0.41mmol). The reaction mixture is stirred at room temperature over aweekend, and then filtered. The obtained filtrate is purified with asemi-preparative HPLC using a gradient of 0-48% B (gradient curve 4) togive(6bR,10aS)-8-decanoyloxymethyl-8-[4-(4-fluoro-phenyl)-4-oxo-butyl]-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-iumformate (20 mg, 25% yield). UPLC retention time: 3.29 min. ESI-MS (m/z,positive mode): 578.3.

EXAMPLE 1B Synthesis of(6bR,10aS)-8-[4-(4-fluoro-phenyl)-4-oxo-butyl]-8-isopropoxycarbonyloxymethyl-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-iumformate

To a solution of the4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluorophenyl)-butan-1-one(48.0 mg, 0.12 mmol) in acetonitrile (2.0 mL) is added chloromethylisopropyl carbonate (25.0 mg, 0.16 mmol), followed by adding NaI (60.0mg, 0.40 mmol). The reaction mixture is stirred at room temperature overa weekend, and then filtered. The obtained filtrate is purified with asemi-preparative HPLC using a gradient of 0-35% B (gradient curve 4) togive(6bR,10aS)-8-[4-(4-fluoro-phenyl)-4-oxo-butyl]-8-isopropoxycarbonyloxymethyl-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo [1,2,3 -de] quinoxalin-8-ium formate (50 mg, 75%yield). UPLC retention time: 2.49 min. ESI-MS (m/z, positive mode):510.3.

EXAMPLE 1C Synthesis of(6bR,10aS)-8-(2,2-dimethyl-propionyloxymethyl)-8-[4-(4-fluoro-phenyl)-4-oxo-butyl]-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-iumformate

To a solution of the4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluorophenyl)-butan-1-one(49.0 mg, 0.12 mmol) in acetonitrile (3.0 mL) is added chloromethylpivalate (19 μL, 0.12 mmol), followed by adding NaI (50.0 mg, 0.33mmol). The reaction mixture is stirred at room temperature overnight,and then filtered. The obtained filtrate is purified with asemi-preparative HPLC using a gradient of 0-35% B (gradient curve 4) togive(6bR,10aS)-8-(2,2-dimethyl-propionyloxymethyl)-8-[4-(4-fluoro-phenyl)-4-oxo-butyl]-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo [1,2,3 -de]quinoxalin-8-ium formate. UPLC retentiontime: 2.48 min ESI-MS (m/z, positive mode): 508.3.

EXAMPLE 1D Synthesis of(6bR,10aS)-8-[4-(4-fluoro-phenyl)-4-oxo-butyl]-8-hexylcarbamoyloxymethyl-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-iumformate

A solution of chloromethyl carbonochloridate (1.0 mL) in CH₂Cl₂ (10 mL)is cooled to -10 ° C., and then a solution of hexan-1-amine (1.3 mL) andpyridine (0.9 mL) in CH₂Cl₂ (2.5 mL) is added dropwise. The reactionmixture is gradually warmed up to room temperature and then stirred atroom temperature for 4 h. The mixture is washed with HCl (1N, 5.0 mL),H₂O (20 mL) and Saturated NaHCO₃ (5.0 mL), successively, and then driedover MgSO₄. After the solvents are removed, the obtained crudechloromethyl hexylcarbamate is used directly in the next step withoutfurther purification.

To a solution of the4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluorophenyl)-butan-1-one(54 mg, 0.14 mmol) in acetonitrile (1.0 mL) is added crude chloromethylhexylcarbamate (86 mg, 0.41 mmol), followed by adding NaI (65 mg, 0.41mmol). The reaction mixture is stirred at room temperature overnight,and then filtered. The obtained filtrate is purified with asemi-preparative HPLC using a gradient of 0-30% B (gradient curve 4) togive(6bR,10aS)-8-[4-(4-fluoro-phenyl)-4-oxo-butyl]-8-hexylcarbamoyloxymethyl-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-iumformate. UPLC retention time: 2.04 min. ESI-MS (m/z, positive mode):551.3.

EXAMPLE 2 Pharmacokinetic Evaluation of the Prodrugs in Rats

Pharmacokinetic Evaluation of the Prodrugs may be carried as describedor similarly described below or in WO 2011/084846, the contents of whichare incorporated by reference in their entirety.

Animals: Male Sprague-Dawley rats (approximately 24 rats) may be used ineach study. Rats may be housed 2 per cage with ad libitum chow andwater. Environmental conditions in the housing room may be 64-67° F.,30% to 70% relative humidity, and 12:12-h light:dark cycle.

Test Compounds: An amount of each test compound may be suspended in thevehicle to yield a suspension comprising the equivalent of 3 mg of thecompound in free base and non-prodrug form, in 0.3 mL.

Pharmacokinetics study: Rats may be dosed 1M by means of a 23 gauge, 1in. needle with 1 cc syringe. 0.3 mL suspension may be withdrawn fromthe vial containing the test compound. The rat may be injected in themuscles of the hind limb after anesthesia with isotlourane. Bloodsamples may be collected via a lateral tail vein after brief anesthesiawith isoflourane. A 27½G needle and 1 cc syringe without ananticoagulant may be used for the blood collection. Approximately 250 μLof whole blood may be collected at each sampling time point of 6 hours,24 hours and 2, 5, 7, 9, 12, 14 days after administration. Approximately450 μL of whole blood may be collected at sampling time points of 21, 28and 35 days. Once collected, whole blood may immediately be transferredto tubes containing K₂ EDTA, inverted 10-15 times and immediately placedon ice. The tubes may be centrifuged for 2 minutes at >14,000×g (11500RPM using Eppendorf Centrifuge 5417C, F45-30-11 rotor) at 4-8° C. toseparate plasma. Plasma samples may be transferred to labeled plaintubes (MICROTAINER®; MFG# BD5962) and stored frozen at <−70° C.

Data Analysis: Drug concentrations in plasma samples may be analyzed byliquid chromatography-mass spectroscopy using appropriate parameters foreach compound. Half-life, volume of distribution, clearance, maximalconcentration, and AUC may be calculated by using WinNonlin software,version 5.2 (Pharsight, St. Louis, Mo.).

The Results will show that the prodrug compounds of the invention have alonger T_(max) and/or T_(1/2) than the parent compound (e.g., compoundof Formula Q, e.g., wherein X is —C(CH₃)— and Y is —C(O)— or the activecompound hereinbefore described).

1. A compound of Formula II:

wherein: Y is —C(O)—, —O— or —C(H)(OR⁴)—; R⁴ is H or —C(O)—C₁₋₂₁ alkyl;R⁵ is —C(O)—O—C(R^(a))(R^(b))(R^(c)) or —C(R⁶)(R⁷)—O—C(O)—R⁸; R⁸ is—C(R^(a))(R^(b))(R^(c)), —O—C(R^(a))(R^(b))(R^(c)) or —N(R^(d))(R^(e));R^(a), R^(b) and R^(c) are independently H or C₁₋₂₄alkyl; R^(d) andR^(e) are independently H or C₁₋₂₄alkyl; and R⁶ and R⁷ are independentlyH or C₁₋₆alkyl; in free or salt form.
 2. The compound according to claim1, wherein: Y is —C(O)— or —O—; R⁵ is —C(O)—O—C(R^(a))(R^(b))(R^(c));R^(a), R^(b) and R^(c) are independently H or C₁₋₂₄alkyl; in free orsalt form.
 3. The compound according to claim 1, Y is —C(O)— or —O—; R⁵is —C(R⁶)(R⁷)—O—C(O)—R⁸; R⁸ is —C (R^(a))(R^(b))(R^(c)), —O—C(R^(a))(R^(b))(R^(c)) or —N(R^(d))(R^(e)); R^(a), R^(b) and R^(c) areindependently H or C₁₋₂₄alkyl; R^(d) and R^(e) are independently H orC₁₋₂₄alkyl; R⁶ and R⁷ are independently H or C₁₋₆alkyl; in free or saltform.
 4. (canceled)
 5. A pharmaceutical composition comprising thecompound according to claim 1, wherein the salt form is apharmaceutically acceptable salt form, or the compound of Formula Q:

wherein W is —N(H)—, or —N(CH₃)—; and Y is C(═O), or —O—, in free orpharmaceutically acceptable salt form, in admixture with apharmaceutically acceptable diluent or carrier.
 6. The pharmaceuticalcomposition according to claim 5, comprising a vehicle comprising aviscosity enhancing agent.
 7. The pharmaceutical composition accordingto claim 6, wherein the viscosity enhancing agent is sodium carboxymethylcellulose.
 8. A pharmaceutical composition comprising (i) acompound according to claim 1, wherein the salt form is apharmaceutically acceptable salt form, or the compound of Formula Q:

wherein W is —N(H)—, or —N(CH₃)—; and Y is —C(═O), or —O—, in free orpharmaceutically acceptable salt form; and (ii) a polymeric matrix. 9.The pharmaceutical composition according to claim 8, wherein thepolymeric matrix is a biodegradable poly(d,l-lactide-co-glycolide)microsphere.
 10. The pharmaceutical composition according to claim 9, inadmixture with a pharmaceutically acceptable diluent or carrier.
 11. Thepharmaceutical composition according to claim 8, wherein saidcomposition releases the active compound over a period of about 7 days,about 14 days, about 30 days, about 60 days or about 90 days.
 12. Acomposition or device comprising (a) a gelatin capsule containing thecompound as described in claim 5; (b) a multilayer wall superposed onthe gelatin capsule comprising, in outward order from the capsule: (i) abarrier layer, (ii) an expandable layer, and (iii) a semipermeablelayer; and (c) an orifice formed or formable through the wall.
 13. Acomposition or device comprising (a) two or more layers, said two ormore layers comprising a first layer and a second layer, said firstlayer comprising the compound as described in claim 5, and said secondlayer comprising a polymer; (b) an outer wall surrounding said two ormore layers; and (c) an orifice in said outer wall.
 14. A method for thetreatment or prophylaxis of a central nervous system disorder,comprising administering to a patient in need thereof an effectiveamount of the compound according to claim
 1. 15. The method according toclaim 14, wherein said disorder is selected from a group consisting ofobesity, anxiety, depression, psychosis, schizophrenia, sleep disorderssexual disorders, sexual disorders, migraine, conditions associated withcephalic pain, social phobias, agitation in dementia, agitation inautism and related autistic disorders, and gastrointestinal disorderssuch as dysfunction of the gastrointestinal tract motility.
 16. Themethod according to claim 14, wherein said disorder is a disorderinvolving serotonin 5-HT₂A, dopamine D2 and/or serotonin reuptaketransporter (SERT) pathway.
 17. The method according to claim 16,wherein said disorder is a disorder selected from the following: (i)psychosis in a patient suffering from depression; (2) depression in apatient suffering from psychosis; (3) mood disorders associated withpsychosis; and (4) sleep disorders associated with psychosis.
 18. Themethod according to claim 15, wherein the disorder is psychosis.
 19. Themethod according to claim 15, wherein the disorder is schizophrenia. 20.The method according to claim 15, wherein the disorder is depression.21.-28. (canceled)
 29. The compound according to claim 2, wherein Y is—C(O)—.
 30. The compound according to claim 3, wherein Y is —C(O)—. 31.The composition according to claim 8, wherein the compound is thecompound of Formula Q.
 32. The composition according to claim 31,wherein W is —N(CH₃)— and Y is —C(═O).